How an organism dies is a fundamental yet poorly understood question in biology. An organism can die of many causes, including stress‐induced phenoptosis, also defined as organismic death that is ...regulated by its genome‐encoded programs. The mechanism of stress‐induced phenoptosis is still largely unknown. Here, we show that transient but severe freezing‐thaw stress (FTS) in Caenorhabditis elegans induces rapid and robust phenoptosis that is regulated by G‐protein coupled receptor (GPCR) signaling. RNAi screens identify the GPCR‐encoding fshr‐1 in mediating transcriptional responses to FTS. FSHR‐1 increases ligand interaction upon FTS and activates a cyclic AMP‐PKA cascade leading to a genetic program to promote organismic death under severe stress. FSHR‐1/GPCR signaling up‐regulates the bZIP‐type transcription factor ZIP‐10, linking FTS to expression of genes involved in lipid remodeling, proteostasis, and aging. A mathematical model suggests how genes may promote organismic death under severe stress conditions, potentially benefiting growth of the clonal population with individuals less stressed and more reproductively privileged. Our studies reveal the roles of FSHR‐1/GPCR‐mediated signaling in stress‐induced gene expression and phenoptosis in C. elegans, providing empirical new insights into mechanisms of stress‐induced phenoptosis with evolutionary implications.
C. elegans rapidly dies upon the exposure to severe freezing‐thaw stress in a regulated fashion (stress‐induced phenoptosis). Signaling from G‐protein‐coupled receptor FSHR‐1 promotes stress‐induced gene expression and phenoptosis. Findings are of implications to the evolutionary kin selection theory and the disposable soma hypothesis of aging.
Evolution by natural selection results in biological traits that enable organismic adaptation and survival under various stressful environments. External stresses can be sometimes too severe to ...overcome, leading to organismic death either because of failure in adapting to such stress, or alternatively, through a regulated form of organismic death (phenoptosis). While regulated cell deaths, including apoptosis, have been extensively studied, little is known about the molecular and cellular mechanisms underlying phenoptosis and its evolutionary significance for multicellular organisms. In this article, we review documented phenomena and mechanistic evidence emerging from studies of stress-induced phenoptosis in the multicellular organism
C. elegans
and stress-induced deaths at cellular levels in organisms ranging from bacteria to mammals, focusing on abiotic and pathogen stresses. Genes and signaling pathways involved in phenoptosis appear to promote organismic death during severe stress and aging, while conferring fitness and immune defense during mild stress and early life, consistent with their antagonistic pleiotropy actions. As cell apoptosis during development can shape tissues and organs, stress-induced phenoptosis may also contribute to possible benefits at the population level, through mechanisms including kin selection, abortive infection, and soma-to-germline resource allocation. Current models can generate experimentally testable predictions and conceptual frameworks with implications for understanding both stress-induced phenoptosis and natural aging.
Cells adapt to temperature shifts by adjusting levels of lipid desaturation and membrane fluidity. This fundamental process occurs in nearly all forms of life, but its mechanism in eukaryotes is ...unknown. We discovered that the evolutionarily conserved Caenorhabditis elegans gene acdh-11 (acyl-CoA dehydrogenase ACDH) facilitates heat adaptation by regulating the lipid desaturase FAT-7. Human ACDH deficiency causes the most common inherited disorders of fatty acid oxidation, with syndromes that are exacerbated by hyperthermia. Heat upregulates acdh-11 expression to decrease fat-7 expression. We solved the high-resolution crystal structure of ACDH-11 and established the molecular basis of its selective and high-affinity binding to C11/C12-chain fatty acids. ACDH-11 sequesters C11/C12-chain fatty acids and prevents these fatty acids from activating nuclear hormone receptors and driving fat-7 expression. Thus, the ACDH-11 pathway drives heat adaptation by linking temperature shifts to regulation of lipid desaturase levels and membrane fluidity via an unprecedented mode of fatty acid signaling.
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•ACDH-11 upregulation sequesters C11/12 fatty acids to drive heat adaptation•Decreased C11/12 fatty acids downregulate FAT-7 fatty acid desaturase•Reduced levels of membrane desaturated fatty acids reduce membrane fluidity•The acdh-11 phenotype models a thermo-sensitive syndrome caused by ACDH deficiency
Cells must adjust lipid saturation levels to maintain membrane fluidity upon temperature change. A highly conserved lipid metabolism protein links these processes in C. elegans by sequestering fatty acids from the transcriptional activator of a lipid desaturase when temperatures rise.
Dysregulation of collagen production and secretion contributes to aging and tissue fibrosis of major organs. How procollagen proteins in the endoplasmic reticulum (ER) route as specialized cargos for ...secretion remains to be fully elucidated. Here, we report that TMEM39, an ER-localized transmembrane protein, regulates production and secretory cargo trafficking of procollagen. We identify the C. elegans ortholog TMEM-39 from an unbiased RNAi screen and show that deficiency of tmem-39 leads to striking defects in cuticle collagen production and constitutively high ER stress response. RNAi knockdown of the tmem-39 ortholog in Drosophila causes similar defects in collagen secretion from fat body cells. The cytosolic domain of human TMEM39A binds to Sec23A, a vesicle coat protein that drives collagen secretion and vesicular trafficking. TMEM-39 regulation of collagen secretion is independent of ER stress response and autophagy. We propose that the roles of TMEM-39 in collagen secretion and ER homeostasis are likely evolutionarily conserved.
DNA methylation has been traditionally viewed as a highly stable epigenetic mark in postmitotic cells. However, postnatal brains appear to show stimulus-induced methylation changes, at least in a few ...identified CpG dinucleotides. How extensively the neuronal DNA methylome is regulated by neuronal activity is unknown. Using a next-generation sequencing-based method for genome-wide analysis at single-nucleotide resolution, we quantitatively compared the CpG methylation landscape of adult mouse dentate granule neurons in vivo before and after synchronous neuronal activation. About 1.4% of 219,991 CpGs measured showed rapid active demethylation or de novo methylation. Some modifications remained stable for at least 24 h. These activity-modified CpGs showed a broad genomic distribution with significant enrichment in low-CpG density regions, and were associated with brain-specific genes related to neuronal plasticity. Our study implicates modification of the neuronal DNA methylome as a previously underappreciated mechanism for activity-dependent epigenetic regulation in the adult nervous system.
Low temperatures delay aging and promote longevity in many organisms. However, the metabolic and homeostatic aspects of low-temperature-induced longevity remain poorly understood. Here, we show that ...lipid homeostasis regulated by Caenorhabditis elegans Mediator 15 (MDT-15 or MED15), a transcriptional coregulator, is essential for low-temperature-induced longevity and proteostasis. We find that inhibition of mdt-15 prevents animals from living long at low temperatures. We show that MDT-15 up-regulates fat-7, a fatty acid desaturase that converts saturated fatty acids (SFAs) to unsaturated fatty acids (UFAs), at low temperatures. We then demonstrate that maintaining a high UFA/SFA ratio is essential for proteostasis at low temperatures. We show that dietary supplementation with a monounsaturated fatty acid, oleic acid (OA), substantially mitigates the short life span and proteotoxicity in mdt-15(-) animals at low temperatures. Thus, lipidostasis regulated by MDT-15 appears to be a limiting factor for proteostasis and longevity at low temperatures. Our findings highlight the crucial roles of lipid regulation in maintaining normal organismal physiology under different environmental conditions.
The mammalian brain exhibits diverse types of neural plasticity, including activity-dependent neurogenesis in the adult hippocampus. How transient activation of mature neurons leads to long-lasting ...modulation of adult neurogenesis is unknown. Here we identify Gadd45b as a neural activity-induced immediate early gene in mature hippocampal neurons. Mice with Gadd45b deletion exhibit specific deficits in neural activity-induced proliferation of neural progenitors and dendritic growth of newborn neurons in the adult hippocampus. Mechanistically, Gadd45b is required for activity-induced DNA demethylation of specific promoters and expression of corresponding genes critical for adult neurogenesis, including brain-derived neurotrophic factor and fibroblast growth factor. Thus, Gadd45b links neuronal circuit activity to epigenetic DNA modification and expression of secreted factors in mature neurons for extrinsic modulation of neurogenesis in the adult brain.
Epigenetic mechanisms regulate cell differentiation during embryonic development and also serve as important interfaces between genes and the environment in adulthood. Neurogenesis in adults, which ...generates functional neural cell types from adult neural stem cells, is dynamically regulated by both intrinsic state-specific cell differentiation cues and extrinsic neural niche signals. Epigenetic regulation by DNA and histone modifiers, non-coding RNAs and other self-sustained mechanisms can lead to relatively long-lasting biological effects and maintain functional neurogenesis throughout life in discrete regions of the mammalian brain. Here, we review recent evidence that epigenetic mechanisms carry out diverse roles in regulating specific aspects of adult neurogenesis and highlight the implications of such epigenetic regulation for neural plasticity and disorders.
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) protein that can be secreted and protects dopamine neurons and cardiomyocytes from ER stress and apoptosis. ...The mechanism of action of extracellular MANF has long been elusive. From a genetic screen for mutants with abnormal ER stress response, we identified the gene Y54G2A.23 as the evolutionarily conserved C. elegans MANF orthologue. We find that MANF binds to the lipid sulfatide, also known as 3-O-sulfogalactosylceramide present in serum and outer-cell membrane leaflets, directly in isolated forms and in reconstituted lipid micelles. Sulfatide binding promotes cellular MANF uptake and cytoprotection from hypoxia-induced cell death. Heightened ER stress responses of MANF-null C. elegans mutants and mammalian cells are alleviated by human MANF in a sulfatide-dependent manner. Our results demonstrate conserved roles of MANF in sulfatide binding and ER stress response, supporting sulfatide as a long-sought lipid mediator of MANF's cytoprotection.
Neural stem cells (NSCs) are present not only during the embryonic development but also in the adult brain of all mammalian species, including humans. Stem cell niche architecture in vivo enables ...adult NSCs to continuously generate functional neurons in specific brain regions throughout life. The adult neurogenesis process is subject to dynamic regulation by various physiological, pathological and pharmacological stimuli. Multipotent adult NSCs also appear to be intrinsically plastic, amenable to genetic programing during normal differentiation, and to epigenetic reprograming during de-differentiation into pluripotency. Increasing evidence suggests that adult NSCs significantly contribute to specialized neural functions under physiological and pathological conditions. Fully understanding the biology of adult NSCs will provide crucial insights into both the etiology and potential therapeutic interventions of major brain disorders. Here, we review recent progress on adult NSCs of the mammalian central nervous system, including topics on their identity, niche, function, plasticity, and emerging roles in cancer and regenerative medicine.
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