Une expérience surprenante avec les sciences! Les Visites insolites du CNRS vous proposent chaque année des expériences uniques, en groupe restreint, au cœur des laboratoires de recherche pour vivre des moments privilégiés avec les scientifiques.

Si on vous dit « microbes » ou « bactéries », vous pensez généralement aux pathogènes, causes de nombreuses maladies et de grandes épidémies dans l’histoire de l’humanité (peste, lèpre, tuberculose…) ? Et pourtant, les micro-organismes ne sont pas toujours nos ennemis, certaines bactéries sont même à l’origine de nombreux antibiotiques ! Si lors de leurs découvertes dans les années 1950-1970, nous avons cru gagner la bataille contre les bactéries pathogènes, ces dernières résistent et ne sont plus sensibles aux antibiotiques actuels. Alors comment recherche-t-on de nouveaux antibiotiques ? Comment étudie-t-on les bactéries qui les fabriquent ? Quels sont les mécanismes de résistance des bactéries pathogènes ? Peut-on faire fabriquer de nouveaux antibiotiques à des bactéries ? Venez découvrir la réponse à certaines de ces questions au travers d’observations et de discussions avec des membres du laboratoire !

more information: https://visitesinsolites.cnrs.fr/visite/sous-la-loupe-du-laboratoire-secrets-et-defis-des-antibiotiques/

PhD student Audrey Ntadambanya from the Department of Cell Biology, won the prize for best presentation at the Photosciences 2024 conference.

PhD student Audrey Ntadambanya, supervised by Marcelina Cardoso Dos Santos, won the prize for best presentation at the Photosciences 2024 conference. She was rewarded for her presentation, which was judged to be of high scientific quality and delivered with great enthusiasm and skill. Audrey's thesis work focuses on the development of new nanosensors based on quantum dot nanoparticles to resolve biomolecular interactions at the sub-nanometre scale. The prize was a scientific book selected by the winner. Furthermore, Audrey was able to attend the conference due to financial support from OI BioProbe for participation in international conferences.

more information: https://new.societechimiquedefrance.fr/divisions/photochimie-photophysique-et-photosciences/important-dates/

Contact: marcelina.cardoso-dos-santos@i2bc.paris-saclay.fr

The I2BC will be present at the Fête de la Science on 5 and 6 October 2024 at ENS Paris-Saclay (4 avenue des sciences- Gif sur Yvette) on the theme ‘Ocean of knowledge’. The Microbiology Department and the Crystallography Platform will each have a stand entitled ‘Can bacteria swim?’ and ‘Making and observing protein crystals’, where the public can carry out experiments, look under a microscope and take part in games.

more information: https://www.fetedelascience.fr/

Contact: catherine.grandclement@i2bc.paris-saclay.fr

Early Steps of DNA Recombination: AlphaFold2 breaks a lock.

The human MRN nuclease, formed by the association of two proteins, Mre11 and Rad50, is a key player in homologous recombination and meiosis, two processes that utilize DNA break repair mechanisms. In eukaryotes, the Mre11 nuclease is equipped with a molecular lock that controls the activation of the enzyme: its activation is triggered during certain phases of the cell cycle (entry into G2, when DNA is duplicated to allow for the recombination process), when the lock is phosphorylated. This locking protein is called CtIP in humans and Sae2 in the yeast Saccharomyces cerevisiae. It is a protein with a largely disordered structure, which remained a significant challenge for structural characterization for a number of years.

In a study published in Molecular Cell, teams from I2BC, the Curie Institute, and IRB shed light on how the human MRN nuclease functions. The I2BC team modeled the structure of the yeast MRN complex using the AlphaFold2 algorithm. Interestingly, the program hesitates when modeling between two states: inactive (auto-inhibited) and active. Notably, the addition of phosphorylated Sae2 favors the active conformation in AlphaFold2’s predictions: Sae2 appears to unlock the MRN complex by establishing a synergistic set of interactions centered on the phosphorylation of a serine residue in Sae2. The structural predictions obtained with AlphaFold2, supported by in vitro and in vivo experiments, highlight that the phosphorylated Sae2/CtIP protein creates a network of interactions with MRN that promotes the release of its auto-inhibition.

All these findings illustrate how an apparently disordered protein can lift the auto-inhibition of a nuclease and thus control the switch between different repair pathways, which is important in humans for cell cycle progression and meiosis.

More information: https://www.sciencedirect.com/science/article/pii/S1097276524004428?via%3Dihub

Contact:  Raphaël GUEROIS  raphael.guerois@i2bc.paris-saclay.fr

Unveiling a new property of bacteriophage-host interaction in the context of multicellular aggregate dynamics – A multidisciplinary study involving three departments from I2BC (Genomes, Microbiology, and Virology) and a team from MICALIS.

Streptomyces are renowned for their prolific production of specialized metabolites with applications in medicine and agriculture. These multicellular bacteria present a sophisticated developmental cycle, and play a key role in soil ecology. Little is known about the impact of Streptomyces-phage on bacterial physiology. In this study, we investigated the conditions governing the expression and production of ‘Samy’, a prophage found in Streptomyces ambofaciens ATCC 23877. This siphoprophage is produced simultaneously with the activation of other mobile genetic elements. Remarkably, the presence and production of Samy increases bacterial dispersal under in vitro stress conditions. Altogether, this study unveiled a new property of a bacteriophage infection in the context of multicellular aggregate dynamics.

More information: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002725

Contact:  Stéphanie BURY-MONE stephanie.bury-mone@i2bc.paris-saclay.fr

Researchers from the I2BC, the CNRGH (CEA, National Center of Human Genomics Research), and the University of Edinburgh have revealed how the BAF chromatin remodeler changes the structure and accessibility of genetic material by producing subnucleosomal particles. These findings are published in Nature Structural and Molecular Biology.

Mutations in genes encoding subunits of the BAF complex (BRG1/BRM-associated factors, also known as the SWI/SNF complex) are associated with 20% of human cancers, making this complex the second most frequently mutated factor after the p53 tumor suppressor.
The human genome exists in cells in the form of chromatin, composed of nucleosomes that condense and protect the genetic material. The nucleosomes represent a physical barrier for transcription factors and molecular machinery that regulate gene expression. The BAF complex is known for controlling chromatin opening at gene transcription regulatory elements. Until now, it was believed that the role of the BAF complex was to dissociate the nucleosomes to allow the transcription factors to access DNA.
Using a method that allows them to differentiate histone-free DNA fragments from nucleosomes and histone-containing particles smaller than nucleosomes (subnucleosomes), researchers coordinated by Matthieu Gérard (I2BC) revealed that the BAF complex facilitates the recruitment of the master transcription factor OCT4 using two distinct strategies: i) by generating the well-known histone-free DNA regions, which OCT4 binds if its target DNA motif is present; and ii) by producing a new class of subnucleosomal particles containing 50 to 80 base pairs associated with histones.
They show that the subnucleosomes act as a recruitment platform for OCT4 independently of the presence of its DNA motif. They identify in this publication a molecular mechanism in which the interaction between OCT4 and the subnucleosomes leads to a spectacular expansion of the OCT4 genomic binding interval. This mechanism aims to project OCT4 activity in chromatin opening within a genomic interval up to one order of magnitude larger than the interval bound by OCT4 on histone-free DNA.
This study suggests two main determinants for recruiting transcription factors onto the mammalian genome: the genetic determinant, the transcription factor motif within histone-free DNA, and an epigenetic determinant, which corresponds to the subnucleosomes produced by the BAF complex.

More information: https://www.nature.com/articles/s41594-024-01344-0

Contact: Matthieu GERARD matthieu.gerard@i2bc.paris-saclay.fr

In search of the hidden gene cluster: Synteruptor, a new tool for identifying bacterial genomic islands and exploring their content in the quest for new specialized metabolism gene clusters.

Microbial specialized metabolite biosynthetic gene clusters (SMBGCs) are a formidable source of natural products of pharmaceutical interest. With the multiplication of genomic data available, very efficient bioinformatic tools for automatic SMBGC detection have been developed. Nevertheless, most of these tools identify SMBGCs based on sequence similarity with enzymes typically involved in specialised metabolism and thus may miss SMBGCs coding for undercharacterised enzymes. In this article, we present Synteruptor (https://bioi2.i2bc.paris-saclay.fr/synteruptor), a program that identifies genomic islands, known to be enriched in SMBGCs, in the genomes of closely related species. With this tool, we identified a SMBGC in the genome of Streptomyces ambofaciens ATCC23877, undetected by antiSMASH, the well-known and most used tool for SMBGC identification, prior to antiSMASH 5. We experimentally demonstrated that this SMBGC directs the biosynthesis of two metabolites, one of which was identified as sphydrofuran. Synteruptor is also a valuable resource for the delineation of individual SMBGCs within antiSMASH regions that may encompass multiple clusters, and for refining the boundaries of these SMBGCs.

More information: https://doi.org/10.1093/nargab/lqae069

Contact: Sylvie LAUTRU <sylvie.lautru@i2bc.paris-saclay.fr> & Olivier LESPINET <olivier.lespinet@i2bc.paris-saclay.fr>

The UPR sensors show high plasticity in sensing physiological alterations by closely reporting the variations in ER Ca2+ levels. Through this mechanisms cells could rapidly adapt stress response signaling pathways to variations in ER homeostasis.

The unfolded protein response (UPR) is a widespread signal transduction pathway triggered by endoplasmic reticulum (ER) stress. Because calcium (Ca2+) is a key factor in the maintenance of ER homeostasis, massive Ca2+ depletion of the ER is a potent inducer of ER stress. Although moderate changes in ER Ca2+ drive the ubiquitous Ca2+ signaling pathways, a possible incremental relationship between UPR activation and Ca2+ changes has yet to be described. Here, we determine the sensitivity and time-dependency of activation of the three ER stress sensors, IRE1α, PERK and ATF6α in response to controlled changes in the concentration of ER Ca2+ in human cultured cells. Combining Ca2+ imaging, FRAP experiments, biochemical analyses and mathematical modeling, we uncover a non-linear rate of activation of the IRE1α branch of UPR, as compared to the PERK and ATF6α branches that become activated gradually with time and are sensitive to more important ER Ca2+ depletions. However, the three arms are all activated within a 1h timescale. The model predicted the deactivation of PERK and IRE1α upon refilling the ER with Ca2+. Accordingly, we showed that ER Ca2+ replenishment leads to the complete reversion of IRE1α and PERK phosphorylation in less than 15 min, thus revealing the highly plastic character of the activation of the upstream UPR sensors. In conclusion, our results reveal a dynamic and dose-sensitive Ca2+-dependent activation/deactivation cycle of UPR induction, which could tightly control cell fate upon acute and/or chronic stress.

More information: https://doi.org/10.1093/pnasnexus/pgae229

Contact: Ilaria Pontisso (ilaria.pontisso@i2bc.paris-saclay.fr)

We are seeking one highly motivated PhD candidate to join our research team at the Institute for Integrative Biology of the Cell (I2BC).

The project entitled “Selective autophagy receptors in viral antigen presentation” is an exciting opportunity to explore the intersection
of immunology and virology.

More information: https://www.i2bc.paris-saclay.fr/equipe-autophagy-and-antiviral-immunity/

Contact: Arnaud Moris (arnaud.moris@i2bc.paris-saclay.fr)

Researchers from the AMIG team (I2BC department), in collaboration with the IRB (Switzerland), have modeled the interaction between HROB and the helicases MCM8-MCM9, some mutations of which predispose individuals to infertility or cancer. They demonstrate that HROB promotes the catalytic activity of the MCM8-MCM9 complex but does not play a role in its recruitment or stability.

The proteins MCM8 and MCM9 have recently been discovered as involved in multiple processes, normal and pathological, related to DNA replication, meiosis, homologous recombination, and mismatch repair. These proteins are helicases that have the ability to move along DNA and separate the two DNA strands. Variants of these proteins may predispose carriers to disorders such as infertility and cancer. In 2019, a third partner, HROB, was identified as associated with these two helicases without its mechanisms of action being understood. Since HROB is capable of interacting with DNA, three functional hypotheses can be considered:
1) HROB participates in the recruitment of helicases on DNA,
2) HROB stabilizes the assembly of MCM8 and MCM9 on DNA,
3) HROB promotes the catalytic activity of pre-assembled helicases.

In a study published in the journal Nature Communications, researchers from the AMIG team at the Institute of Integrative Biology of the Cell (I2BC) collaborated with a team from the Institute of Research in Biomedicine (IRB) in Switzerland to establish different structural models of the MCM8-MCM9-HROB complex. Guided by these models, a set of simple and compensatory mutations allowed the dissection of the functional role of HROB. The teams showed that only the third hypothesis was correct and that HROB is an essential factor for activating the MCM8-MCM9 helicase but not for its recruitment or stability. The structural model suggests that by transiently altering the conformation of a MCM9 subunit, HROB stimulates the translocation of the helicase along the DNA. Based on this model, it was even possible to design mutations that increase the efficiency of the helicase in the presence of HROB.

More information: https://www.nature.com/articles/s41467-024-47936-8

Contact: Raphaël Guerois raphael.guerois@i2bc.paris-saclay.fr 

“Ménage à trois”: coordination of lipid transfer, metabolism and storage at the new mitochondria-ER-lipid droplet junction.

Over the past two decades, we have witnessed a growing appreciation for the importance of membrane contact sites (CS) in facilitating direct communication between organelles. CS are tiny regions where the membranes of two organelles meet but do not fuse and allow the transfer of metabolites between organelles, playing crucial roles in the coordination of cellular metabolic activities. The significant advancements in imaging techniques, and molecular and cell biology research has revealed that CS are more complex than what originally thought, as they are extremely dynamics, they can remodel their shape, composition and functions in accord to metabolic and environmental changes, and can occur between more than two organelles. In this review, for the Special Issue “Lipid droplets, metabolic hubs in health and disease“ in FEBS Letters, Vera F. Monteiro-Cardoso and Francesca Giordano describe how recent studies led to the identification of a three-way mitochondria-ER-lipid droplet CS and discuss the emerging functions of these contacts in maintaining lipid storage, homeostasis and balance. They also summarize properties and functions of key protein components localized at the mitochondria-ER-lipid droplet interface, with a special focus on lipid transfer proteins. Understanding tripartite CS is essential for unraveling the complexities of inter-organelle communication and cooperation within cells.

more information: https://febs.onlinelibrary.wiley.com/doi/10.1002/1873-3468.14893

contact: Francesca GIORDANO <francesca.giordano@i2bc.paris-saclay.fr>

How enteric bacteria handle a cold snap

Bacteria that inhabit warm-blooded hosts, particularly enteric pathogens and commensals, often spend prolonged periods outside their hosts in cooler environments. The transition from a warm to a cold external environment typically occurs abruptly when bacteria are released from the host. Understanding how these microorganisms rapidly adapt and thrive at low temperatures is crucial for defining their persistence on contaminated surfaces and their spread to humans and animals.
At the molecular level, the primary effect of cold shock on bacterial physiology is the inhibition of protein synthesis, largely due to increased RNA structuring. Bacteria respond by synthesizing a set of RNA chaperone proteins that either unfold RNA secondary structures or degrade misfolded, untranslatable RNA. The synthesis of these “cold-shock response” (CSR) proteins is driven by cold-induced secondary structures in the 5’ untranslated regions of their mRNAs, which expose ribosome binding sites and facilitate translation initiation. As CSR proteins accumulate, their RNA unfolding activity on their own mRNAs acts as a negative feedback mechanism to reduce synthesis once bacteria acclimate to low temperatures.
In a study published in Molecular Cell, researchers from the I2BC, in collaboration with a group from the CBM, CNRS, Orleans, demonstrated that the very RNA structures that activate CSP mRNA translation act earlier to prevent premature transcription termination by sequestering the binding sites for the termination factor Rho. Remarkably, these conditional terminators function as dual-input, antagonistic riboswitches that regulate Rho access to mRNA based on temperature and CSR protein concentration. Together with established post-transcriptional mechanisms, this allows tight and timely control of CSR gene expression: an initial burst during cold shock followed by attenuation during acclimation. This work establishes a novel paradigm for how RNA thermosensors modulate gene expression.

more information: https://www.sciencedirect.com/science/article/pii/S1097276524006324

Contact: nara.figueroa@i2bc.paris-saclay.fr lionello.bossi@i2bc.paris-saclay.fr

This chapter reviews in the insect world the integration of the carbohydrate-lipid metabolic axis at the entire body level

Carbohydrates and lipids integrate into a complex metabolic network that is essential to maintain homeostasis. In insects, as in most metazoans, dietary carbohydrates are taken up as monosaccharides whose excess is toxic, even at relatively low concentrations. To cope with this toxicity, monosaccharides are stored either as glycogen or neutral lipids, the latter constituting a quasi-unlimited energy store. Breakdown of these stores in response to energy demand depends on insect species and on several physiological parameters. In this chapter, we review the multiple metabolic pathways and strategies linking carbohydrates and lipids that insects utilize to respond to nutrient availability, food scarcity or physiological activities.

more information: https://www.ncbi.nlm.nih.gov/pubmed/39192070

Contact: jacques.montagne@i2bc.paris-saclay.fr

Want to learn more about the third domain of life, the Archaea? Join us at I2BC for an annual symposium gathering French research community studying archaea.

The Archaea 2024 symposium, organised by the SFBBM's GT-Archées, is intended to bring together the entire French scientific community to discuss and exchange ideas on unifying themes relating to the importance and place of Archaea, the third domain of living organisms, in ecosystems, evolution and the fundamental processes of life. The scientific community is seeking to elucidate the fundamental molecular mechanisms at work in these microorganisms, the diversity of their viruses, and the adaptive limits of living organisms in relation to the environment. Archaea have been the subject of study from a variety of disciplinary perspectives, including those of biochemists, microbiologists, evolutionists, molecular biologists and also from the perspective of industry. Archaea are now being regarded as essential models for understanding the processes that underpin the functioning of living organisms.

more information: https://archaea2024.sciencesconf.org/

Contact: tamara.basta@i2bc.paris-saclay.fr

Analysis of the consequences of the deletion of genes involved in nitrogen metabolism on the content of phospholipids or of storage lipids of Streptomyces coelicolor illustrates the complex links exiting between carbon, nitrogen and phosphate metabolisms.

Since nitrogen (N) limitation is known to be an important trigger of storage lipid / triacylglycerol (TAG) accumulation, in most microorganisms, we assessed the global lipid content of 21 strains derived from Streptomyces coelicolor deleted for genes involved in N metabolism. These strains were grown in the classical R2YE medium that is N and phosphate (P) limited. Seven of these strains had a higher TAG content than the original strain. These strains were either deleted for genes encoding proteins involved 1) in polyamine degradation (GlnA2/SCO2241, GlnA3/SCO6962, GlnA4/SCO1613); 2) in protein degradation (Pup/SCO1646); 3) in the regulation of nitrogen metabolism (GlnE/SCO2234 and GlnK/SCO5584) or 4) encoding the global regulator DasR/SCO5231 that controls negatively the degradation of N-acetylglucosamine, a constituent of peptidoglycan. Five of these strains, with the exception of the glnA2 and pup mutants, had a lower cardiolipin (CL) content than the original strain. This suggested that in these strains the biosynthesis of TAG, molecule devoided of (P) groups is prevalent over that of CL that bears 2 (P) groups, thus allowing higher (P) availability. The deletion of pup, glnA2, glnA3, and glnA4 was correlated, in Pi limitation, with an increase in the total production of the blue polyketide actinorhodin (ACT), whereas ACT production was strongly reduced in the glnA3 mutant in (P) proficiency and was totally abolished in the dasR mutant in both (P) conditions. Altogether, our data suggest that N limitation linked to the deletion of genes mentioned above results into high oxidative stress that triggers storage of acetylCoA as TAG to reduce the activity of the oxidative metabolism, generator of oxidative stress, as well as the biosynthesis of ACT that has anti-oxidant properties. At last, the reduced ACT biosynthesis of the glnA3 mutant, is thought to be due to its high spermine and spermidine content, molecules known to protect the cell against oxidative stress.

More information: doi.org/10.3390/microorganisms12081560

Contact: Marie-Joëlle VIROLLE  marie-joelle.virolle@i2bc.paris-saclay.fr

TLN468 promotes PTC readthrough by preferentially incorporating specific tRNAs based on the mutation.

Nonsense mutations account for 12 % of cystic fibrosis (CF) cases. The presence of a premature termination codon (PTC) leads to gene inactivation, which can be countered by the use of drugs stimulating PTC readthrough, restoring production of the full-length protein. We recently identified a new readthrough inducer, TLN468, more efficient than gentamicin.
We measured the readthrough induced by these two drugs with different cystic fibrosis transmembrane conductance regulator (CFTR) PTCs. We then determined the amino acids inserted at the S1196X, G542X, W846X and E1417X PTCs of CFTR during readthrough induced by gentamicin or TLN468. TLN468 significantly promoted the incorporation of one specific amino acid, whereas gentamicin did not greatly modify the pro- portions of the various amino acids incorporated relative to basal conditions. The function of the engineered missense CFTR channels corresponding to these four PTCs was assessed with and without potentiator. For the recoded CFTR, except for E1417Q and G542W, the PTC readthrough induced by TLN468 allowed the expression of CFTR variants that were correctly processed and had significant activity that was enhanced by CFTR modu- lators. These results suggest that it would be relevant to assess the therapeutic benefit of TLN468 PTC sup- pression in combination with CFTR modulators in preclinical assays.

More information: https://www.cysticfibrosisjournal.com/article/S1569-1993(24)00802-6/fulltext

Contact: Olivier NAMY  olivier.namy@i2bc.paris-saclay.fr

Phanie is a phi-29 like phage that protects its genome inside non-infectious podovirus-like particles, requiring acquisition of the tail from a myovirus helper for production of infectious chimeras.

Viruses of bacteria (bacteriophages or phages) display a remarkable genomic diversity reflecting the complex interaction they have built with their host during evolution. In addition to fully infectious viral particles, different types of genetic elements were described to require a helper phage for production of infectious virions. The genome of these satellite parasite sequences may share sequences with phages or be more closely related to non-viral chromosome islands. We describe a new mode of satellite phage dependence on a helper phage. Phanie, like the genetically related Bacillus subtilis phage phi29, replicates its linear dsDNA by a protein primed-mechanism and protects it inside podovirus-like particles. However, these particles are defective, requiring acquisition of the tail from a myovirus helper for production of infectious virions. Formation of chimeras between a phi29-like podovirus and a helper contractile tail reveals an unexpected association between very different bacterial viruses.

More information: https://journals-asm-org.insb.bib.cnrs.fr/doi/10.1128/jvi.00667-24

Contact: Christine Pourcel christine.pourcel@i2bc.paris-saclay.fr

October 14th -16th

Site Henri Moissan Université Paris-Saclay Orsay

More information: https://www.universite-paris-saclay.fr/evenements/physchemcell2024

Researchers at I2BC and their collaborators have conducted an extensive functional analysis of a highly conserved Tail Completion Protein (TCP) in the assembly and infectivity of tailed bacteriophages.

Their investigation highlights the role of bacteriophage SPP1 TCP gp16.1 as a structural element of the tail, serving two distinct purposes. Firstly, gp16.1 assists assembly of the tail interface that binds to the phage capsid. Secondly, it ensures proper delivery of phage DNA to the bacterial cytoplasm.
In the absence of gp16.1, assembled viral particles are undistinguishable from wild-type virions and eject DNA efficiently in vitro. However, upon interaction with the host bacteria, they release their DNA into the extracellular space. Transfer of DNA from the viral particle to the bacterial cytoplasm requires prior localized digestion of the bacterial cell wall, likely facilitated by the tail tip, and the formation of a lipophilic channel in the bacterial membrane for DNA passage. Successful infection depends on precise timing, involving phage binding to the receptor, creating a pathway for DNA passage through the cell envelope, and DNA exit from the particle into the bacterial cytoplasm.
The authors propose that the gp16.1 critical function is achieved by its positioning at the tail end proximal to the capsid to form a complex with the Tape Measure Protein (TMP) and the Tail Tube Protein (TTP). These interactions conceivably regulate the timing of TMP and DNA release. This could result of narrowing the internal diameter of the tail tube to retain the TMP, slowing down release of the TMP and DNA until a continuous hydrophilic channel forms between the tail and the bacterial cytoplasm. Their study unravels the dual role of gp16.1 in tail assembly and in delivery of viral DNA into bacteria. Both functions are most likely exerted by the large superfamily of TCPs that are essential components of phages with long tails.

More information: https://www.nature.com/articles/s42003-024-06221-6

Contact: Isabelle Auzat isabelle.auzat@i2bc.paris-saclay.fr 

The production of unhealthy eggs leads to improved maternal stress resilience and proteostasis in C. elegans. This study identifies the nuclear hormone receptor NHR-49 as a critical regulator that is activated by elevated fat stores and acts by potentiating the heat shock response.

The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in Caenorhabditis elegans We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

More information: https://genesdev.cshlp.org/content/early/2024/05/30/gad.351829.124

Contact: Ambre Sala  ambre.sala@i2bc.paris-saaclay.fr