1.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201912375. doi: 10.1073/pnas.1912375117. [Epub ahead of print]
DBC1, p300, HDAC3, and Siah1 coordinately regulate ELL stability and function for expression of its target genes.
Basu S1, Barad M1, Yadav D1, Nandy A1, Mukherjee B2, Sarkar J3, Chakrabarti P3, Mukhopadhyay S2, Biswas D4.
Abstract
Among all of the Super Elongation Complex (SEC) components, ELL1 (also known as ELL) is the only bona fide elongation factor that directly stimulates transcription elongation by RNA polymerase II. However, the mechanism(s) of functional regulation of ELL1 (referred to as ELL hereafter), through its stabilization, is completely unknown. Here, we report a function of human DBC1 in regulating ELL stability involving HDAC3, p300, and Siah1. Mechanistically, we show that p300-mediated site-specific acetylation increases, whereas HDAC3-mediated deacetylation decreases, ELL stability through polyubiquitylation by the E3 ubiquitin ligase Siah1. DBC1 competes with HDAC3 for the same binding sites on ELL and thus increases its acetylation and stability. Knockdown of DBC1 reduces ELL levels and expression of a significant number of genes, including those involved in glucose metabolism. Consistently, Type 2 diabetes patient-derived peripheral blood mononuclear cells show reduced expression of DBC1 and ELL and associated key target genes required for glucose homeostasis. Thus, we describe a pathway of regulating stability and functions of key elongation factor ELL for expression of diverse sets of genes, including ones that are linked to Type 2 diabetes pathogenesis.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
DBC1; ELL; acetylation; transcription; ubiquitylation
2.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201915370. doi: 10.1073/pnas.1915370117. [Epub ahead of print]
Tuning ferromagnetism at room temperature by visible light.
Abstract
Most digital information today is encoded in the magnetization of ferromagnetic domains. The demand for ever-increasing storage space fuels continuous research for energy-efficient manipulation of magnetism at smaller and smaller length scales. Writing a bit is usually achieved by rotating the magnetization of domains of the magnetic medium, which relies on effective magnetic fields. An alternative approach is to change the magnetic state directly by acting on the interaction between magnetic moments. Correlated oxides are ideal materials for this because the effects of a small external control parameter are amplified by the electronic correlations. Here, we present a radical method for reversible, light-induced tuning of ferromagnetism at room temperature using a halide perovskite/oxide perovskite heterostructure. We demonstrate that photoinduced charge carriers from the [Formula: see text] photovoltaic perovskite efficiently dope the thin [Formula: see text] film and decrease the magnetization of the ferromagnetic state, allowing rapid rewriting of the magnetic bit. This manipulation could be accomplished at room temperature; hence this opens avenues for magnetooptical memory devices.
KEYWORDS:
CH3NH3PbI3; LSMO; heat-assisted magnetic recording; magnetism tuning
3.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201912505. doi: 10.1073/pnas.1912505117. [Epub ahead of print]
Mitotic and pheromone-specific intrinsic polarization cues interfere with gradient sensing in Saccharomyces cerevisiae.
Abstract
Polarity decisions are central to many processes, including mitosis and chemotropism. In Saccharomyces cerevisiae, budding and mating projection (MP) formation use an overlapping system of cortical landmarks that converges on the small G protein Cdc42. However, pheromone-gradient sensing must override the Rsr1-dependent internal polarity cues used for budding. Using this model system, we asked what happens when intrinsic and extrinsic spatial cues are not aligned. Is there competition, or collaboration? By live-cell microscopy and microfluidics techniques, we uncovered three previously overlooked features of this signaling system. First, the cytokinesis-associated polarization patch serves as a polarity landmark independently of all known cues. Second, the Rax1-Rax2 complex functions as a pheromone-promoted polarity cue in the distal pole of the cells. Third, internal cues remain active during pheromone-gradient tracking and can interfere with this process, biasing the location of MPs. Yeast defective in internal-cue utilization align significantly better than wild type with artificially generated pheromone gradients.
KEYWORDS:
Rax1; Rsr1; chemotropism; cytokinesis; signal integration
4.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201921344. doi: 10.1073/pnas.1921344117. [Epub ahead of print]
Lysosomal degradation products induce Coxiella burnetii virulence.
Newton P1, Thomas DR1, Reed SCO2, Lau N1, Xu B3, Ong SY4, Pasricha S4, Madhamshettiwar PB5, Edgington-Mitchell LE6,7, Simpson KJ5,8, Roy CR2, Newton HJ9.
Abstract
Coxiella burnetii is an intracellular pathogen that replicates in a lysosome-like vacuole through activation of a Dot/Icm-type IVB secretion system and subsequent translocation of effectors that remodel the host cell. Here a genome-wide small interfering RNA screen and reporter assay were used to identify host proteins required for Dot/Icm effector translocation. Significant, and independently validated, hits demonstrated the importance of multiple protein families required for endocytic trafficking of the C. burnetii-containing vacuole to the lysosome. Further analysis demonstrated that the degradative activity of the lysosome created by proteases, such as TPP1, which are transported to the lysosome by receptors, such as M6PR and LRP1, are critical for C. burnetii virulence. Indeed, the C. burnetii PmrA/B regulon, responsible for transcriptional up-regulation of genes encoding the Dot/Icm apparatus and a subset of effectors, induced expression of a virulence-associated transcriptome in response to degradative products of the lysosome. Luciferase reporter strains, and subsequent RNA-sequencing analysis, demonstrated that particular amino acids activate the C. burnetii PmrA/B two-component system. This study has further enhanced our understanding of C. burnetii pathogenesis, the host-pathogen interactions that contribute to bacterial virulence, and the different environmental triggers pathogens can sense to facilitate virulence.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
Coxiella burnetii; Dot/Icm secretion system; amino acid sensing; siRNA screen; virulence regulation
5.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201918386. doi: 10.1073/pnas.1918386117. [Epub ahead of print]
Fluctuation-response inequality out of equilibrium.
Abstract
We present an approach to response around arbitrary out-of-equilibrium states in the form of a fluctuation-response inequality (FRI). We study the response of an observable to a perturbation of the underlying stochastic dynamics. We find that the magnitude of the response is bounded from above by the fluctuations of the observable in the unperturbed system and the Kullback-Leibler divergence between the probability densities describing the perturbed and the unperturbed system. This establishes a connection between linear response and concepts of information theory. We show that in many physical situations, the relative entropy may be expressed in terms of physical observables. As a direct consequence of this FRI, we show that for steady-state particle transport, the differential mobility is bounded by the diffusivity. For a "virtual" perturbation proportional to the local mean velocity, we recover the thermodynamic uncertainty relation (TUR) for steady-state transport processes. Finally, we use the FRI to derive a generalization of the uncertainty relation to arbitrary dynamics, which involves higher-order cumulants of the observable. We provide an explicit example, in which the TUR is violated but its generalization is satisfied with equality.
KEYWORDS:
entropy; nonequilibrium thermodynamics; response; transport
6.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201920582. doi: 10.1073/pnas.1920582117. [Epub ahead of print]
Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses.
Abstract
The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85β subunit. Here we present the mechanism underlying the molecular recognition of the p85β subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85β of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1ED) undergoes a conformational change to bind p85β. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1ED exists in a dynamic equilibrium between p85β-binding-competent and -incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1ED proteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85β. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1ED can result in the faster hijacking of p85β compared to Ud NS1ED, although the former has a lower affinity to p85β than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins.
KEYWORDS:
conformational dynamics; influenza virus; nonstructural protein 1
7.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202001686. doi: 10.1073/pnas.2001686117. [Epub ahead of print]
Interactions between changing climate and biodiversity: Shaping humanity's future.
8.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202000172. doi: 10.1073/pnas.2000172117. [Epub ahead of print]
IPyA glucosylation mediates light and temperature signaling to regulate auxin-dependent hypocotyl elongation in Arabidopsis.
Abstract
Auxin is a class of plant hormone that plays a crucial role in the life cycle of plants, particularly in the growth response of plants to ever-changing environments. Since the auxin responses are concentration-dependent and higher auxin concentrations might often be inhibitory, the optimal endogenous auxin level must be closely controlled. However, the underlying mechanism governing auxin homeostasis remains largely unknown. In this study, a UDP-glycosyltransferase (UGT76F1) was identified from Arabidopsis thaliana, which participates in the regulation of auxin homeostasis by glucosylation of indole-3-pyruvic acid (IPyA), a major precursor of the auxin indole-3-acetic acid (IAA) biosynthesis, in the formation of IPyA glucose conjugates (IPyA-Glc). In addition, UGT76F1 was found to mediate hypocotyl growth by modulating active auxin levels in a light- and temperature-dependent manner. Moreover, the transcription of UGT76F1 was demonstrated to be directly and negatively regulated by PIF4, which is a key integrator of both light and temperature signaling pathways. This study sheds a light on the trade-off between IAA biosynthesis and IPyA-Glc formation in controlling auxin levels and reveals a regulatory mechanism for plant growth adaptation to environmental changes through glucosylation of IPyA.
KEYWORDS:
Arabidopsis thaliana; auxin; glycosylation
9.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202003198. doi: 10.1073/pnas.2003198117. [Epub ahead of print]
Correction for Hsu et al., Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration.
[No authors listed]
Erratum for
- Phenotypical microRNA screen reveals a noncanonical role of CDK2 in regulating neutrophil migration. [Proc Natl Acad Sci U S A. 2019]
10.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201921388. doi: 10.1073/pnas.1921388117. [Epub ahead of print]
Longitudinal dynamics of the human B cell response to the yellow fever 17D vaccine.
Wec AZ1, Haslwanter D2, Abdiche YN3, Shehata L1, Pedreño-Lopez N4, Moyer CL5, Bornholdt ZA5, Lilov A1, Nett JH1, Jangra RK2, Brown M1, Watkins DI4, Ahlm C6, Forsell MN6, Rey FA7, Barba-Spaeth G7, Chandran K2, Walker LM8.
Abstract
A comprehensive understanding of the development and evolution of human B cell responses induced by pathogen exposure will facilitate the design of next-generation vaccines. Here, we utilized a high-throughput single B cell cloning technology to longitudinally track the human B cell response to the yellow fever virus 17D (YFV-17D) vaccine. The early memory B cell (MBC) response was mediated by both classical immunoglobulin M (IgM) (IgM+CD27+) and switched immunoglobulin (swIg+) MBC populations; however, classical IgM MBCs waned rapidly, whereas swIg+ and atypical IgM+ and IgD+ MBCs were stable over time. Affinity maturation continued for 6 to 9 mo following vaccination, providing evidence for the persistence of germinal center activity long after the period of active viral replication in peripheral blood. Finally, a substantial fraction of the neutralizing antibody response was mediated by public clones that recognize a fusion loop-proximal antigenic site within domain II of the viral envelope glycoprotein. Overall, our findings provide a framework for understanding the dynamics and complexity of human B cell responses elicited by infection and vaccination.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
B cell memory; antibody responses; antiviral vaccination; monoclonal antibody; yellow fever virus
11.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201910402. doi: 10.1073/pnas.1910402117. [Epub ahead of print]
Vulnerable robots positively shape human conversational dynamics in a human-robot team.
Abstract
Social robots are becoming increasingly influential in shaping the behavior of humans with whom they interact. Here, we examine how the actions of a social robot can influence human-to-human communication, and not just robot-human communication, using groups of three humans and one robot playing 30 rounds of a collaborative game (n = 51 groups). We find that people in groups with a robot making vulnerable statements converse substantially more with each other, distribute their conversation somewhat more equally, and perceive their groups more positively compared to control groups with a robot that either makes neutral statements or no statements at the end of each round. Shifts in robot speech have the power not only to affect how people interact with robots, but also how people interact with each other, offering the prospect for modifying social interactions via the introduction of artificial agents into hybrid systems of humans and machines.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
conversational dynamics; groups and teams; human–robot interaction
12.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201906466. doi: 10.1073/pnas.1906466117. [Epub ahead of print]
Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation.
Marreiros R1, Müller-Schiffmann A1, Trossbach SV1, Prikulis I1, Hänsch S2, Weidtkamp-Peters S2, Moreira AR3, Sahu S3, Soloviev I3, Selvarajah S3, Lingappa VR3, Korth C4.
Abstract
Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection of Rag knockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of α-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced α-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 in Rag knockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated α-synuclein or DISC1 that may be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding.
KEYWORDS:
DISC1; Parkinson’s disease; influenza; protein misfolding; α-synuclein
13.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201911816. doi: 10.1073/pnas.1911816117. [Epub ahead of print]
CD300f immunoreceptor is associated with major depressive disorder and decreased microglial metabolic fitness.
Lago N1, Kaufmann FN2, Negro-Demontel ML1,3, Alí-Ruiz D1, Ghisleni G4, Rego N5, Arcas-García A6, Vitureira N1,7, Jansen K4, Souza LM4, Silva RA4, Lara DR8, Pannunzio B1,3, Abin-Carriquiry JA9, Amo-Aparicio J10, Martin-Otal C6, Naya H6, McGavern DB11, Sayós J6, López-Vales R10, Kaster MP2, Peluffo H12,3.
Abstract
A role for microglia in neuropsychiatric diseases, including major depressive disorder (MDD), has been postulated. Regulation of microglial phenotype by immune receptors has become a central topic in many neurological conditions. We explored preclinical and clinical evidence for the role of the CD300f immune receptor in the fine regulation of microglial phenotype and its contribution to MDD. We found that a prevalent nonsynonymous single-nucleotide polymorphism (C/T, rs2034310) of the human CD300f receptor cytoplasmic tail inhibits the protein kinase C phosphorylation of a threonine and is associated with protection against MDD, mainly in women. Interestingly, CD300f-/- mice displayed several characteristic MDD traits such as augmented microglial numbers, increased interleukin 6 and interleukin 1 receptor antagonist messenger RNA, alterations in synaptic strength, and noradrenaline-dependent and persistent depressive-like and anhedonic behaviors in females. This behavioral phenotype could be potentiated inducing the lipopolysaccharide depression model. RNA sequencing and biochemical studies revealed an association with impaired microglial metabolic fitness. In conclusion, we report a clear association that links the function of the CD300f immune receptor with MDD in humans, depressive-like and anhedonic behaviors in female mice, and altered microglial metabolic reprogramming.
KEYWORDS:
CD300; RNA-seq; depression; immunereceptor; microglia
14.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202002727. doi: 10.1073/pnas.2002727117. [Epub ahead of print]
Correction for Shi et al., Deep elastic strain engineering of bandgap through machine learning.
[No authors listed]
Erratum for
- Deep elastic strain engineering of bandgap through machine learning. [Proc Natl Acad Sci U S A. 2019]
15.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201916903. doi: 10.1073/pnas.1916903117. [Epub ahead of print]
Active learning narrows achievement gaps for underrepresented students in undergraduate science, technology, engineering, and math.
Theobald EJ1, Hill MJ2, Tran E2, Agrawal S3, Arroyo EN4, Behling S5, Chambwe N6, Cintrón DL2, Cooper JD2, Dunster G2, Grummer JA2, Hennessey K2, Hsiao J2, Iranon N7, Jones L 2nd2, Jordt H2, Keller M2, Lacey ME2, Littlefield CE5, Lowe A2, Newman S8,9, Okolo V2, Olroyd S2, Peecook BR2, Pickett SB10, Slager DL2, Caviedes-Solis IW2, Stanchak KE2, Sundaravardan V11, Valdebenito C2, Williams CR12, Zinsli K2, Freeman S1.
Abstract
We tested the hypothesis that underrepresented students in active-learning classrooms experience narrower achievement gaps than underrepresented students in traditional lecturing classrooms, averaged across all science, technology, engineering, and mathematics (STEM) fields and courses. We conducted a comprehensive search for both published and unpublished studies that compared the performance of underrepresented students to their overrepresented classmates in active-learning and traditional-lecturing treatments. This search resulted in data on student examination scores from 15 studies (9,238 total students) and data on student failure rates from 26 studies (44,606 total students). Bayesian regression analyses showed that on average, active learning reduced achievement gaps in examination scores by 33% and narrowed gaps in passing rates by 45%. The reported proportion of time that students spend on in-class activities was important, as only classes that implemented high-intensity active learning narrowed achievement gaps. Sensitivity analyses showed that the conclusions are robust to sampling bias and other issues. To explain the extensive variation in efficacy observed among studies, we propose the heads-and-hearts hypothesis, which holds that meaningful reductions in achievement gaps only occur when course designs combine deliberate practice with inclusive teaching. Our results support calls to replace traditional lecturing with evidence-based, active-learning course designs across the STEM disciplines and suggest that innovations in instructional strategies can increase equity in higher education.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
achievement gaps; active learning; heads-and-hearts hypothesis; individual-participant data metaanalysis; underrepresented minorities
16.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201921037. doi: 10.1073/pnas.1921037117. [Epub ahead of print]
Ostrich eggshell bead strontium isotopes reveal persistent macroscale social networking across late Quaternary southern Africa.
Abstract
Hunter-gatherer exchange networks dampen subsistence and reproductive risks by building relationships of mutual support outside local groups that are underwritten by symbolic gift exchange. Hxaro, the system of delayed reciprocity between Ju/'hoãn individuals in southern Africa's Kalahari Desert, is the best-known such example and the basis for most analogies and models of hunter-gatherer exchange in prehistory. However, its antiquity, drivers, and development remain unclear, as they do for long-distance exchanges among African foragers more broadly. Here we show through strontium isotope analyses of ostrich eggshell beads from highland Lesotho, and associated strontium isoscape development, that such practices stretch back into the late Middle Stone Age. We argue that these exchange items originated beyond the macroband from groups occupying the more water-stressed subcontinental interior. Tracking the emergence and persistence of macroscale, transbiome social networks helps illuminate the evolution of social strategies needed to thrive in stochastic environments, strategies that in our case study show persistence over more than 33,000 y.
KEYWORDS:
late Quaternary; ostrich eggshell beads; social networks; southern Africa; strontium isotope analysis
17.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201911868. doi: 10.1073/pnas.1911868117. [Epub ahead of print]
Sitting, squatting, and the evolutionary biology of human inactivity.
Abstract
Recent work suggests human physiology is not well adapted to prolonged periods of inactivity, with time spent sitting increasing cardiovascular disease and mortality risk. Health risks from sitting are generally linked with reduced levels of muscle contractions in chair-sitting postures and associated reductions in muscle metabolism. These inactivity-associated health risks are somewhat paradoxical, since evolutionary pressures tend to favor energy-minimizing strategies, including rest. Here, we examined inactivity in a hunter-gatherer population (the Hadza of Tanzania) to understand how sedentary behaviors occur in a nonindustrial economic context more typical of humans' evolutionary history. We tested the hypothesis that nonambulatory rest in hunter-gatherers involves increased muscle activity that is different from chair-sitting sedentary postures used in industrialized populations. Using a combination of objectively measured inactivity from thigh-worn accelerometers, observational data, and electromygraphic data, we show that hunter-gatherers have high levels of total nonambulatory time (mean ± SD = 9.90 ± 2.36 h/d), similar to those found in industrialized populations. However, nonambulatory time in Hadza adults often occurs in postures like squatting, and we show that these "active rest" postures require higher levels of lower limb muscle activity than chair sitting. Based on our results, we introduce the Inactivity Mismatch Hypothesis and propose that human physiology is likely adapted to more consistently active muscles derived from both physical activity and from nonambulatory postures with higher levels of muscle contraction. Interventions built on this model may help reduce the negative health impacts of inactivity in industrialized populations.
KEYWORDS:
cardiovascular disease; hunter-gatherer; physical activity; posture; sedentary
18.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201916725. doi: 10.1073/pnas.1916725117. [Epub ahead of print]
Two systems for thinking about others' thoughts in the developing brain.
Abstract
Human social interaction crucially relies on the ability to infer what other people think. Referred to as Theory of Mind (ToM), this ability has long been argued to emerge around 4 y of age when children start passing traditional verbal ToM tasks. This developmental dogma has recently been questioned by nonverbal ToM tasks passed by infants younger than 2 y of age. How do young children solve these tests, and what is their relation to the later-developing verbal ToM reasoning? Are there two different systems for nonverbal and verbal ToM, and when is the developmental onset of mature adult ToM? To address these questions, we related markers of cortical brain structure (i.e., cortical thickness and surface area) of 3- and 4-y-old children to their performance in novel nonverbal and traditional verbal TM tasks. We showed that verbal ToM reasoning was supported by cortical surface area and thickness of the precuneus and temporoparietal junction, classically involved in ToM in adults. Nonverbal ToM reasoning, in contrast, was supported by the cortical structure of a distinct and independent neural network including the supramarginal gyrus also involved in emotional and visual perspective taking, action observation, and social attention or encoding biases. This neural dissociation suggests two systems for reasoning about others' minds-mature verbal ToM that emerges around 4 y of age, whereas nonverbal ToM tasks rely on different earlier-developing possibly social-cognitive processes.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
Theory of Mind; brain development; cortical thickness; false belief; gray matter
19.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201911761. doi: 10.1073/pnas.1911761117. [Epub ahead of print]
Killer whale presence drives bowhead whale selection for sea ice in Arctic seascapes of fear.
Abstract
The effects of predator intimidation on habitat use and behavior of prey species are rarely quantified for large marine vertebrates over ecologically relevant scales. Using state space movement models followed by a series of step selection functions, we analyzed movement data of concurrently tracked prey, bowhead whales (Balaena mysticetus; n = 7), and predator, killer whales (Orcinus orca; n = 3), in a large (63,000 km2), partially ice-covered gulf in the Canadian Arctic. Our analysis revealed pronounced predator-mediated shifts in prey habitat use and behavior over much larger spatiotemporal scales than previously documented in any marine or terrestrial ecosystem. The striking shift from use of open water (predator-free) to dense sea ice and shorelines (predators present) was exhibited gulf-wide by all tracked bowheads during the entire 3-wk period killer whales were present, constituting a nonconsumptive effect (NCE) with unknown energetic or fitness costs. Sea ice is considered quintessential habitat for bowhead whales, and ice-covered areas have frequently been interpreted as preferred bowhead foraging habitat in analyses that have not assessed predator effects. Given the NCEs of apex predators demonstrated here, however, unbiased assessment of habitat use and distribution of bowhead whales and many marine species may not be possible without explicitly incorporating spatiotemporal distribution of predation risk. The apparent use of sea ice as a predator refuge also has implications for how bowhead whales, and likely other ice-associated Arctic marine mammals, will cope with changes in Arctic sea ice dynamics as historically ice-covered areas become increasingly ice-free during summer.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
nonconsumptive effects; predator−prey dynamics; risk effects; state space model; trait-mediated interactions
20.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201921640. doi: 10.1073/pnas.1921640117. [Epub ahead of print]
Cryo-EM structure of rhinovirus C15a bound to its cadherin-related protein 3 receptor.
Abstract
Infection by Rhinovirus-C (RV-C), a species of Picornaviridae Enterovirus, is strongly associated with childhood asthma exacerbations. Cellular binding and entry by all RV-C, which trigger these episodes, is mediated by the first extracellular domain (EC1) of cadherin-related protein 3 (CDHR3), a surface cadherin-like protein expressed primarily on the apical surfaces of ciliated airway epithelial cells. Although recombinant EC1 is a potent inhibitor of viral infection, there is no molecular description of this protein or its binding site on RV-C. Here we present cryo-electron microscopy (EM) data resolving the EC1 and EC1+2 domains of human CDHR3 complexed with viral isolate C15a. Structure-suggested residues contributing to required interfaces on both EC1 and C15a were probed and identified by mutagenesis studies with four different RV-C genotypes. In contrast to most other rhinoviruses, which bind intercellular adhesion molecule 1 receptors via a capsid protein VP1-specific fivefold canyon feature, the CDHR3 EC1 contacts C15a, and presumably all RV-Cs, in a unique cohesive footprint near the threefold vertex, encompassing residues primarily from viral protein VP3, but also from VP1 and VP2. The EC1+2 footprint on C15a is similar to that of EC1 alone but shows that steric hindrance imposed by EC2 would likely prevent multiprotein binding by the native receptor at any singular threefold vertex. Definition of the molecular interface between the RV-Cs and their receptors provides new avenues that can be explored for potential antiviral therapies.
KEYWORDS:
CDHR3; cadherin; cryo-EM; receptor; rhinovirus C
21.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201916163. doi: 10.1073/pnas.1916163117. [Epub ahead of print]
Cerebellar plasticity and associative memories are controlled by perineuronal nets.
Carulli D1,2,3, Broersen R4,5, de Winter F6, Muir EM7, Mešković M4, de Waal M6, de Vries S6, Boele HJ5, Canto CB4,5, De Zeeuw CI8,5, Verhaagen J1,9.
Abstract
Perineuronal nets (PNNs) are assemblies of extracellular matrix molecules, which surround the cell body and dendrites of many types of neuron and regulate neural plasticity. PNNs are prominently expressed around neurons of the deep cerebellar nuclei (DCN), but their role in adult cerebellar plasticity and behavior is far from clear. Here we show that PNNs in the mouse DCN are diminished during eyeblink conditioning (EBC), a form of associative motor learning that depends on DCN plasticity. When memories are fully acquired, PNNs are restored. Enzymatic digestion of PNNs in the DCN improves EBC learning, but intact PNNs are necessary for memory retention. At the structural level, PNN removal induces significant synaptic rearrangements in vivo, resulting in increased inhibition of DCN baseline activity in awake behaving mice. Together, these results demonstrate that PNNs are critical players in the regulation of cerebellar circuitry and function.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
cerebellum; eyeblink conditioning; learning; perineuronal net; plasticity
22.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202002662. doi: 10.1073/pnas.2002662117. [Epub ahead of print]
Mechanism of murderous mushrooms paves path for parasitic helminth halt.
23.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202001931. doi: 10.1073/pnas.2001931117. [Epub ahead of print]
Bacteria suit up with virus armor.
Chang YW1.
24.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201905178. doi: 10.1073/pnas.1905178117. [Epub ahead of print]
Brain activity forecasts video engagement in an internet attention market.
Abstract
The growth of the internet has spawned new "attention markets," in which people devote increasing amounts of time to consuming online content, but the neurobehavioral mechanisms that drive engagement in these markets have yet to be elucidated. We used functional MRI (FMRI) to examine whether individuals' neural responses to videos could predict their choices to start and stop watching videos as well as whether group brain activity could forecast aggregate video view frequency and duration out of sample on the internet (i.e., on youtube.com). Brain activity during video onset predicted individual choice in several regions (i.e., increased activity in the nucleus accumbens [NAcc] and medial prefrontal cortex [MPFC] as well as decreased activity in the anterior insula [AIns]). Group activity during video onset in only a subset of these regions, however, forecasted both aggregate view frequency and duration (i.e., increased NAcc and decreased AIns)-and did so above and beyond conventional measures. These findings extend neuroforecasting theory and tools by revealing that activity in brain regions implicated in anticipatory affect at the onset of video viewing (but not initial choice) can forecast time allocation out of sample in an internet attention market.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
FMRI; accumbens; forecasting; insula; video
25.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201914324. doi: 10.1073/pnas.1914324117. [Epub ahead of print]
Delayed negative effects of prosocial spending on happiness.
Abstract
Does prosocial behavior promote happiness? We test this longstanding hypothesis in a behavioral experiment that extends the scope of previous research. In our Saving a Life paradigm, every participant either saved one human life in expectation by triggering a targeted donation of 350 euros or received an amount of 100 euros. Using a choice paradigm between two binary lotteries with different chances of saving a life, we observed subjects' intentions at the same time as creating random variation in prosocial outcomes. We repeatedly measured happiness at various delays. Our data weakly replicate the positive effect identified in previous research but only for the very short run. One month later, the sign of the effect reversed, and prosocial behavior led to significantly lower happiness than obtaining the money. Notably, even those subjects who chose prosocially were ultimately happier if they ended up getting the money for themselves. Our findings revealed a more nuanced causal relationship than previously suggested, providing an explanation for the apparent absence of universal prosocial behavior.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
altruism; happiness; prosocial behavior; wellbeing
26.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201913750. doi: 10.1073/pnas.1913750117. [Epub ahead of print]
Trait evolution is reversible, repeatable, and decoupled in the soldier caste of turtle ants.
Abstract
The scope of adaptive phenotypic change within a lineage is shaped by how functional traits evolve. Castes are defining functional traits of adaptive phenotypic change in complex insect societies, and caste evolution is expected to be phylogenetically conserved and developmentally constrained at broad phylogenetic scales. Yet how castes evolve at the species level has remained largely unaddressed. Turtle ant soldiers (genus Cephalotes), an iconic example of caste specialization, defend nest entrances by using their elaborately armored heads as living barricades. Across species, soldier morphotype determines entrance specialization and defensive strategy, while head size sets the specific size of defended entrances. Our species-level comparative analyses of morphotype and head size evolution reveal that these key ecomorphological traits are extensively reversible, repeatable, and decoupled within soldiers and between soldier and queen castes. Repeated evolutionary gains and losses of the four morphotypes were reconstructed consistently across multiple analyses. In addition, morphotype did not predict mean head size across the three most common morphotypes, and head size distributions overlapped broadly across all morphotypes. Concordantly, multiple model-fitting approaches suggested that soldier head size evolution is best explained by a process of divergent pulses of change. Finally, while soldier and queen head size were broadly coupled across species, the level of head size disparity between castes was decoupled from both queen head size and soldier morphotype. These findings demonstrate that caste evolution can be highly dynamic at the species level, reshaping our understanding of adaptive morphological change in complex social lineages.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
Cephalotes; adaptive radiation; niche filling; polymorphism; polyphenism
27.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201920869. doi: 10.1073/pnas.1920869117. [Epub ahead of print]
Optofluidic control of rodent learning using cloaked caged glutamate.
Abstract
Glutamate is the major excitatory neurotransmitter in the brain, and photochemical release of glutamate (or uncaging) is a chemical technique widely used by biologists to interrogate its physiology. A basic prerequisite of these optical probes is bio-inertness before photolysis. However, all caged glutamates are known to have strong antagonism toward receptors of γ-aminobutyric acid, the major inhibitory transmitter. We have developed a caged glutamate probe that is inert toward these receptors at concentrations that are effective for photolysis with violet light. Pharmacological tests in vitro revealed that attachment of a fifth-generation (G5) dendrimer (i.e., cloaking) to the widely used 4-methoxy-7-nitro-indolinyl(MNI)-Glu probe prevented such off-target effects while not changing the photochemical properties of MNI-Glu significantly. G5-MNI-Glu was used with optofluidic delivery to stimulate dopamine neurons of the ventral tegmental area of freely moving mice in a conditioned place-preference protocol so as to mediate Pavlovian conditioning.
KEYWORDS:
GABA-A antagonism; biologically inert; caged glutamate; conditioned place-preference; optofluidics
28.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201920012. doi: 10.1073/pnas.1920012117. [Epub ahead of print]
Nutrient dilution and climate cycles underlie declines in a dominant insect herbivore.
Abstract
Evidence for global insect declines mounts, increasing our need to understand underlying mechanisms. We test the nutrient dilution (ND) hypothesis-the decreasing concentration of essential dietary minerals with increasing plant productivity-that particularly targets insect herbivores. Nutrient dilution can result from increased plant biomass due to climate or CO2 enrichment. Additionally, when considering long-term trends driven by climate, one must account for large-scale oscillations including El Niño Southern Oscillation (ENSO), North Atlantic Oscillation (NAO), and Pacific Decadal Oscillation (PDO). We combine long-term datasets of grasshopper abundance, climate, plant biomass, and end-of-season foliar elemental content to examine potential drivers of abundance cycles and trends of this dominant herbivore. Annual grasshopper abundances in 16- and 22-y time series from a Kansas prairie revealed both 5-y cycles and declines of 2.1-2.7%/y. Climate cycle indices of spring ENSO, summer NAO, and winter or spring PDO accounted for 40-54% of the variation in grasshopper abundance, mediated by effects of weather and host plants. Consistent with ND, grass biomass doubled and foliar concentrations of N, P, K, and Na-nutrients which limit grasshopper abundance-declined over the same period. The decline in plant nutrients accounted for 25% of the variation in grasshopper abundance over two decades. Thus a warming, wetter, more CO2-enriched world will likely contribute to declines in insect herbivores by depleting nutrients from their already nutrient-poor diet. Unlike other potential drivers of insect declines-habitat loss, light and chemical pollution-ND may be widespread in remaining natural areas.
KEYWORDS:
Acrididae; global change; grasshopper; grassland; insect decline
29.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201912501. doi: 10.1073/pnas.1912501117. [Epub ahead of print]
Higher-rank zeta functions and SL n -zeta functions for curves.
Abstract
In earlier papers L.W. introduced two sequences of higher-rank zeta functions associated to a smooth projective curve over a finite field, both of them generalizing the Artin zeta function of the curve. One of these zeta functions is defined geometrically in terms of semistable vector bundles of rank n over the curve and the other one group-theoretically in terms of certain periods associated to the curve and to a split reductive group G and its maximal parabolic subgroup P. It was conjectured that these two zeta functions coincide in the special case when [Formula: see text] and P is the parabolic subgroup consisting of matrices whose final row vanishes except for its last entry. In this paper we prove this equality by giving an explicit inductive calculation of the group-theoretically defined zeta functions in terms of the original Artin zeta function (corresponding to [Formula: see text]) and then verifying that the result obtained agrees with the inductive determination of the geometrically defined zeta functions found by Sergey Mozgovoy and Markus Reineke in 2014.
KEYWORDS:
curves over finite fields; nonabelian zeta function; special permutations; zeta functions; zeta functions for SLn
30.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201918936. doi: 10.1073/pnas.1918936117. [Epub ahead of print]
Visualizing the protons in a metalloenzyme electron proton transfer pathway.
Kwon H1, Basran J2,3, Devos JM4, Suardíaz R1,5, van der Kamp MW5, Mulholland AJ1, Schrader TE6, Ostermann A7, Blakeley MP8, Moody PCE9,3, Raven EL10.
Abstract
In redox metalloenzymes, the process of electron transfer often involves the concerted movement of a proton. These processes are referred to as proton-coupled electron transfer, and they underpin a wide variety of biological processes, including respiration, energy conversion, photosynthesis, and metalloenzyme catalysis. The mechanisms of proton delivery are incompletely understood, in part due to an absence of information on exact proton locations and hydrogen bonding structures in a bona fide metalloenzyme proton pathway. Here, we present a 2.1-Å neutron crystal structure of the complex formed between a redox metalloenzyme (ascorbate peroxidase) and its reducing substrate (ascorbate). In the neutron structure of the complex, the protonation states of the electron/proton donor (ascorbate) and all of the residues involved in the electron/proton transfer pathway are directly observed. This information sheds light on possible proton movements during heme-catalyzed oxygen activation, as well as on ascorbate oxidation.
KEYWORDS:
ascorbate; heme; neutron; peroxidase; proton transfer
31.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201919267. doi: 10.1073/pnas.1919267117. [Epub ahead of print]
The Tol-Pal system is required for peptidoglycan-cleaving enzymes to complete bacterial cell division.
Abstract
Tol-Pal is a multiprotein system present in the envelope of Gram-negative bacteria. Inactivation of this widely conserved machinery compromises the outer membrane (OM) layer of these organisms, resulting in hypersensitivity to many antibiotics. Mutants in the tol-pal locus fail to complete division and form cell chains. This phenotype along with the localization of Tol-Pal components to the cytokinetic ring in Escherichia coli has led to the proposal that the primary function of the system is to promote OM constriction during division. Accordingly, a poorly constricted OM is believed to link the cell chains formed upon Tol-Pal inactivation. However, we show here that cell chains of E. coli tol-pal mutants are connected by an incompletely processed peptidoglycan (PG) layer. Genetic suppressors of this defect were isolated and found to overproduce OM lipoproteins capable of cleaving the glycan strands of PG. Among the factors promoting cell separation in mutant cells was a protein of previously unknown function (YddW), which we have identified as a divisome-localized glycosyl hydrolase that cleaves peptide-free PG glycans. Overall, our results indicate that the cell chaining defect of Tol-Pal mutants cannot simply be interpreted as a defect in OM constriction. Rather, the complex also appears to be required for the activity of several OM-localized enzymes with cell wall remodeling activity. Thus, the Tol-Pal system may play a more general role in coordinating OM invagination with PG remodeling at the division site than previously appreciated.
KEYWORDS:
cell wall; colicin; divisome; peptidoglycan
32.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201916965. doi: 10.1073/pnas.1916965117. [Epub ahead of print]
Intestinal bile acids directly modulate the structure and function of C. difficile TcdB toxin.
Tam J1, Icho S1,2, Utama E1,2, Orrell KE2, Gómez-Biagi RF1,3, Theriot CM4, Kroh HK5, Rutherford SA5, Lacy DB5, Melnyk RA6,2,3.
Abstract
Intestinal bile acids are known to modulate the germination and growth of Clostridioides difficile Here we describe a role for intestinal bile acids in directly binding and neutralizing TcdB toxin, the primary determinant of C. difficile disease. We show that individual primary and secondary bile acids reversibly bind and inhibit TcdB to varying degrees through a mechanism that requires the combined oligopeptide repeats region to which no function has previously been ascribed. We find that bile acids induce TcdB into a compact "balled up" conformation that is no longer able to bind cell surface receptors. Lastly, through a high-throughput screen designed to identify bile acid mimetics we uncovered nonsteroidal small molecule scaffolds that bind and inhibit TcdB through a bile acid-like mechanism. In addition to suggesting a role for bile acids in C. difficile pathogenesis, these findings provide a framework for development of a mechanistic class of C. difficile antitoxins.
KEYWORDS:
C. difficile; bile acid; pathogenesis; structure; toxin
33.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 202003190. doi: 10.1073/pnas.2003190117. [Epub ahead of print]
Correction for Cristopher Bragg et al., Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon in TAF1.
[No authors listed]
Erratum for
34.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201911811. doi: 10.1073/pnas.1911811117. [Epub ahead of print]
Twin-chain polymer hydrogels based on poly(vinyl alcohol) as new advanced tool for the cleaning of modern and contemporary art.
Mastrangelo R1,2, Chelazzi D1,2, Poggi G1,2, Fratini E1,2, Pensabene Buemi L3, Petruzzellis ML3, Baglioni P4,2.
Abstract
Conservation of our cultural heritage is fundamental for conveying to future generations our culture, traditions, and ways of thinking and behaving. Cleaning art, in particular modern/contemporary paintings, with traditional tools could be risky and impractical, particularly on large collections of important works to be transferred to future generations. We report on advanced cleaning systems, based on twin-chain polymer networks made of poly(vinyl alcohol) (PVA) chains, semiinterpenetrated (semi-IPN) with PVA of lower molecular weight (L-PVA). Interpenetrating L-PVA causes a change from gels with oriented channels to sponge-like semi-IPNs with disordered interconnected pores, conferring different gel (and solvent) dynamics. These features grant residue-free, time efficient cleaning capacity and effective dirt capture, defeating risks for the artifact, making possible a safer treatment of important collections, unconceivable with conventional methods. We report as an example the conservation of Jackson Pollock's masterpieces, cleaned in a controlled way, safety and selectivity with unprecedented performance.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
contemporary art; cultural heritage conservation; modern art; poly(vinyl alcohol) hydrogel; semiinterpenetrated gels networks
35.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201916414. doi: 10.1073/pnas.1916414117. [Epub ahead of print]
Mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program.
Vyssokikh MY1, Holtze S2, Averina OA1,3, Lyamzaev KG1,3, Panteleeva AA1, Marey MV4, Zinovkin RA1,3,5, Severin FF1, Skulachev MV1,3, Fasel N6, Hildebrandt TB2, Skulachev VP7.
Abstract
The mitochondria of various tissues from mice, naked mole rats (NMRs), and bats possess two mechanistically similar systems to prevent the generation of mitochondrial reactive oxygen species (mROS): hexokinases I and II and creatine kinase bound to mitochondrial membranes. Both systems operate in a manner such that one of the kinase substrates (mitochondrial ATP) is electrophoretically transported by the ATP/ADP antiporter to the catalytic site of bound hexokinase or bound creatine kinase without ATP dilution in the cytosol. One of the kinase reaction products, ADP, is transported back to the mitochondrial matrix via the antiporter, again through an electrophoretic process without cytosol dilution. The system in question continuously supports H+-ATP synthase with ADP until glucose or creatine is available. Under these conditions, the membrane potential, ∆ψ, is maintained at a lower than maximal level (i.e., mild depolarization of mitochondria). This ∆ψ decrease is sufficient to completely inhibit mROS generation. In 2.5-y-old mice, mild depolarization disappears in the skeletal muscles, diaphragm, heart, spleen, and brain and partially in the lung and kidney. This age-dependent decrease in the levels of bound kinases is not observed in NMRs and bats for many years. As a result, ROS-mediated protein damage, which is substantial during the aging of short-lived mice, is stabilized at low levels during the aging of long-lived NMRs and bats. It is suggested that this mitochondrial mild depolarization is a crucial component of the mitochondrial anti-aging system.
Copyright © 2020 the Author(s). Published by PNAS.
KEYWORDS:
aging; antioxidant; mild depolarization; mitochondria; naked mole rat
36.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201919769. doi: 10.1073/pnas.1919769117. [Epub ahead of print]
Highly efficient organic photovoltaics with enhanced stability through the formation of doping-induced stable interfaces.
Jiang Z1,2, Wang F3,4, Fukuda K5,3, Karki A6, Huang W7, Yu K3, Yokota T2, Tajima K3, Nguyen TQ6, Someya T5,2,3.
Abstract
Flexible organic photovoltaics (OPVs) are promising power sources for wearable electronics. However, it is challenging to simultaneously achieve high efficiency as well as good stability under various stresses. Herein, we demonstrate the fabrication of highly efficient (efficiency, 13.2%) and stable OPVs based on nonfullerene blends by a single-step postannealing treatment. The device performance decreases dramatically after annealing at 90 °C and is fully recovered after annealing at 150 °C. Glass-encapsulated annealed OPVs show good environmental stability with 4.8% loss in efficiency after 4,736 h and an estimated T 80 lifetime (80% of the initial power conversion efficiency) of over 20,750 h in the dark under ambient condition and T 80 lifetime of 1,050 h at 85 °C and 30% relative humidity. This environmental stability is enabled by the synergetic effect of the stable morphology of donor/acceptor blends and thermally stabilized interfaces due to doping. Furthermore, the high efficiency and good stability are almost 100% retained in ultraflexible OPVs and minimodules which are mechanically robust and have long-term operation capability and thus are promising for future self-powered and wearable electronics.
KEYWORDS:
environmental stability; high efficiency; nonfullerene acceptor; organic photovoltaics; ultraflexible devices
37.
Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201909943. doi: 10.1073/pnas.1909943117. [Epub ahead of print]
Spatiotemporal gating of SIRT1 functions by O-GlcNAcylation is essential for liver metabolic switching and prevents hyperglycemia.
Chattopadhyay T1, Maniyadath B1, Bagul HP1, Chakraborty A1, Shukla N1, Budnar S1, Rajendran A2, Shukla A1, Kamat SS2, Kolthur-Seetharam U3.
Abstract
Inefficient physiological transitions are known to cause metabolic disorders. Therefore, investigating mechanisms that constitute molecular switches in a central metabolic organ like the liver becomes crucial. Specifically, upstream mechanisms that control temporal engagement of transcription factors, which are essential to mediate physiological fed-fast-refed transitions are less understood. SIRT1, a NAD+-dependent deacetylase, is pivotal in regulating hepatic gene expression and has emerged as a key therapeutic target. Despite this, if/how nutrient inputs regulate SIRT1 interactions, stability, and therefore downstream functions are still unknown. Here, we establish nutrient-dependent O-GlcNAcylation of SIRT1, within its N-terminal domain, as a crucial determinant of hepatic functions. Our findings demonstrate that during a fasted-to-refed transition, glycosylation of SIRT1 modulates its interactions with various transcription factors and a nodal cytosolic kinase involved in insulin signaling. Moreover, sustained glycosylation in the fed state causes nuclear exclusion and cytosolic ubiquitin-mediated degradation of SIRT1. This mechanism exerts spatiotemporal control over SIRT1 functions by constituting a previously unknown molecular relay. Of note, loss of SIRT1 glycosylation discomposed these interactions resulting in aberrant gene expression, mitochondrial dysfunctions, and enhanced hepatic gluconeogenesis. Expression of nonglycosylatable SIRT1 in the liver abrogated metabolic flexibility, resulting in systemic insulin resistance, hyperglycemia, and hepatic inflammation, highlighting the physiological costs associated with its overactivation. Conversely, our study also reveals that hyperglycosylation of SIRT1 is associated with aging and high-fat-induced obesity. Thus, we establish that nutrient-dependent glycosylation of SIRT1 is essential to gate its functions and maintain physiological fitness.
KEYWORDS:
PGC1α; fed–fast cycle; gluconeogenesis; insulin signaling; ubiquitinylation
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