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The parental environment of C. elegans can have lasting effects on progeny development and immunity. Vitamin B12 exposure in C. elegans has been shown to accelerate development and protect against pathogenic bacteria. Here, we show that parental exposure to dietary vitamin B12 or vitamin B12-producing bacteria results in offspring with accelerated growth that persists for a single generation. During infection with the microsporidian Nematocida parisii , the offspring of worms fed vitamin B12 diets have better reproductive fitness but similar infection levels, suggesting increased tolerance to microsporidian infection. Vitamin B12-induced intergenerational growth acceleration and N. parisii tolerance is dependent upon the methionine biosynthesis pathway. Offspring from vitamin B12-exposed parents are protected from pathogenic Pseudomonas vranovensis and this protection is mediated through methionine biosynthesis and propionyl-CoA breakdown pathways. Our results show how parental microbial diet impacts progeny development through the transfer of vitamin B12 which results in accelerated growth and pathogen tolerance., Competing Interests: The authors declare no competing interests., (© 2024 The Authors.)

Alzheimer's, Parkinson's and Huntington's diseases can be caused by mutations that enhance protein aggregation, but we still do not know enough about the molecular players of these pathways to develop treatments for these devastating diseases. Here, we screen for mutations that might enhance aggregation in Caenorhabditis elegans, to investigate the mechanisms that protect against dysregulated homeostasis. We report that the stomatin homologue UNC-1 activates neurohormonal signalling from the sulfotransferase SSU-1 in ASJ sensory/endocrine neurons. A putative hormone, produced in ASJ, targets the nuclear receptor NHR-1, which acts cell autonomously in the muscles to modulate polyglutamine repeat (polyQ) aggregation. A second nuclear receptor, DAF-12, functions oppositely to NHR-1 to maintain protein homeostasis. Transcriptomics analyses of unc-1 mutants revealed changes in the expression of genes involved in fat metabolism, suggesting that fat metabolism changes, controlled by neurohormonal signalling, contribute to protein homeostasis. Furthermore, the enzymes involved in the identified signalling pathway are potential targets for treating neurodegenerative diseases caused by disrupted protein homeostasis., (© 2023 The Authors. Published under the terms of the CC BY 4.0 license.)

SWItch/sucrose non-fermenting (SWI/SNF) complexes are a family of chromatin remodelers that are conserved across eukaryotes. Mutations in subunits of SWI/SNF cause a multitude of different developmental disorders in humans, most of which have no current treatment options. Here, we identify an alanine-to-valine-causing mutation in the SWI/SNF subunit snfc-5 ( SMARCB1 in humans) that prevents embryonic lethality in Caenorhabditis elegans nematodes harboring a loss-of-function mutation in the SWI/SNF subunit swsn-1 ( SMARCC1/2 in humans). Furthermore, we found that the combination of this specific mutation in snfc-5 and a loss-of-function mutation in either of the E3 ubiquitin ligases ubr-5 ( UBR5 in humans) or hecd-1 ( HECTD1 in humans) can restore development to adulthood in swsn-1 loss-of-function mutants that otherwise die as embryos. Using these mutant models, we established a set of 335 genes that are dysregulated in SWI/SNF mutants that arrest their development embryonically but exhibit near wild-type levels of expression in the presence of suppressor mutations that prevent embryonic lethality, suggesting that SWI/SNF promotes development by regulating some subset of these 335 genes. In addition, we show that SWI/SNF protein levels are reduced in swsn-1; snfc-5 double mutants and partly restored to wild-type levels in swsn-1; snfc-5; ubr-5 triple mutants, consistent with a model in which UBR-5 regulates SWI/SNF levels by tagging the complex for proteasomal degradation. Our findings establish a link between two E3 ubiquitin ligases and SWI/SNF function and suggest that UBR5 and HECTD1 could be potential therapeutic targets for the many developmental disorders caused by missense mutations in SWI/SNF subunits.

In the fight to resist environmental toxins, Caenorhabditis elegans might have co-opted cysteine-synthase-related enzymes that were likely acquired from algae and then integrated them into a hypoxia-signaling pathway to adapt to cyanide., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Despite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress in Caenorhabditis elegans - bacterial infection, eukaryotic infection, osmotic stress, and nutrient stress - across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress -specific, and that they have deleterious tradeoffs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species, we established a core set of 587 genes that exhibited a greater than twofold intergenerational change in expression in response to stress in C. elegans and at least one other species, as well as a set of 37 highly conserved genes that exhibited a greater than twofold intergenerational change in expression in all four species tested. Furthermore, we provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. Lastly, we found that none of the effects we detected of these stresses on C. elegans F1 progeny gene expression persisted transgenerationally three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally., Competing Interests: NB, AW, KF, FB, JP, LS, LB, AR, EM No competing interests declared, (© 2021, Burton et al.)

Ribosome assembly is an essential and conserved process that is regulated at each step by specific factors. Using cryo-electron microscopy (cryo-EM), we visualize the formation of the conserved peptidyl transferase center (PTC) of the human mitochondrial ribosome. The conserved GTPase GTPBP7 regulates the correct folding of 16S ribosomal RNA (rRNA) helices and ensures 2'-O-methylation of the PTC base U3039. GTPBP7 binds the RNA methyltransferase NSUN4 and MTERF4, which sequester H68-71 of the 16S rRNA and allow biogenesis factors to access the maturing PTC. Mutations that disrupt binding of their Caenorhabditis elegans orthologs to the large subunit potently activate mitochondrial stress and cause viability, development, and sterility defects. Next-generation RNA sequencing reveals widespread gene expression changes in these mutant animals that are indicative of mitochondrial stress response activation. We also answer the long-standing question of why NSUN4, but not its enzymatic activity, is indispensable for mitochondrial protein synthesis., Competing Interests: VC, ND, NB, HY, JP, EM, VR No competing interests declared, (© 2021, Chandrasekaran et al.)

Parental exposure to pathogens can prime offspring immunity in diverse organisms. The mechanisms by which this heritable priming occurs are largely unknown. Here we report that the soil bacteria Pseudomonas vranovensis is a natural pathogen of the nematode Caenorhabditis elegans and that parental exposure of animals to P. vranovensis promotes offspring resistance to infection. Furthermore, we demonstrate a multigenerational enhancement of progeny survival when three consecutive generations of animals are exposed to P. vranovensis. By investigating the mechanisms by which animals heritably adapt to P. vranovensis infection, we found that parental infection by P. vranovensis results in increased expression of the cysteine synthases cysl-1 and cysl-2 and the regulator of hypoxia inducible factor rhy-1 in progeny, and that these three genes are required for adaptation to P. vranovensis. These observations establish a CYSL-1, CYSL-2, and RHY-1 dependent mechanism by which animals heritably adapt to infection.

Insulin and insulin-like signaling regulates a broad spectrum of growth and metabolic responses to a variety of internal and environmental stimuli. For example, the inhibition of insulin-like signaling in C. elegans mediates its response to both osmotic stress and starvation. We report that in response to osmotic stress the cytosolic sulfotransferase SSU-1 antagonizes insulin-like signaling and promotes developmental arrest. Both SSU-1 and the DAF-16 FOXO transcription factor, which is activated when insulin signaling is low, are needed to drive specific responses to reduced insulin-like signaling. We demonstrate that SSU-1 functions in a single pair of sensory neurons to control intercellular signaling via the nuclear hormone receptor NHR-1 and promote both the specific transcriptional response to osmotic stress and altered lysophosphatidylcholine metabolism. Our results show the requirement of a sulfotransferase-nuclear hormone receptor neurohormonal signaling pathway for some but not all consequences of reduced insulin-like signaling.

RNA interference (RNAi) is heritable in Caenorhabditis elegans; the progeny of C. elegans exposed to dsRNA inherit the ability to silence genes that were targeted by RNAi in the previous generation. Here we investigate the mechanism of RNAi inheritance in C. elegans. We show that exposure of animals to dsRNA results in the heritable expression of siRNAs and the heritable deposition of histone 3 lysine 9 methylation (H3K9me) marks in progeny. siRNAs are detectable before the appearance of H3K9me marks, suggesting that chromatin marks are not directly inherited but, rather, reestablished in inheriting progeny. Interestingly, H3K9me marks appear more prominently in inheriting progeny than in animals directly exposed to dsRNA, suggesting that germ-line transmission of silencing signals may enhance the efficiency of siRNA-directed H3K9me. Finally, we show that the nuclear RNAi (Nrde) pathway maintains heritable RNAi silencing in C. elegans. The Argonaute (Ago) NRDE-3 associates with heritable siRNAs and, acting in conjunction with the nuclear RNAi factors NRDE-1, NRDE-2, and NRDE-4, promotes siRNA expression in inheriting progeny. These results demonstrate that siRNA expression is heritable in C. elegans and define an RNAi pathway that promotes the maintenance of RNAi silencing and siRNA expression in the progeny of animals exposed to dsRNA.

Invasive cancer cells form dynamic adhesive structures associated with matrix degradation called invadopodia. Calpain 2 is a calcium-dependent intracellular protease that regulates adhesion turnover and disassembly through the targeting of specific substrates such as talin. Here, we describe a novel function for calpain 2 in the formation of invadopodia and in the invasive abilities of breast cancer cells through the modulation of endogenous c-Src activity. Calpain-deficient breast cancer cells show impaired invadopodia formation that is rescued by expression of a truncated fragment of protein tyrosine phosphatase 1B (PTP1B) corresponding to the calpain proteolytic fragment, which indicates that calpain modulates invadopodia through PTP1B. Moreover, PTP1B activity is required for efficient invadopodia formation and breast cancer invasion, which suggests that PTP1B may modulate breast cancer progression through its effects on invadopodia. Collectively, our experiments implicate a novel signaling pathway involving calpain 2, PTP1B, and Src in the regulation of invadopodia and breast cancer invasion.