Research Project
10490496
Project Summary/Abstract: C. elegans surveils the mitochondrion for deficits and couples to an endocrine system of detoxification, innate immunity, and longevity control. This coupling of immunity and detoxification pathways to lifespan regulation has been observed in mice as well. Our analysis of immune responses triggered by mitochondrial dysfunction in C. elegans has revealed that the RNA interference antiviral axis is strongly induced by a variety of mitochondrial defects. The mitochondrial MAVS to RNA helicase system is highly integrated into mammalian NF-kB antiviral cascades; we discovered that in C. elegans mitochondrial dysfunction is coupled to the RNAi antiviral system used by most fungi and plants, and some animals such as C. elegans. Our discovery that protein N-glycosylation by PNG-1/NGLY1 mediates the deamidation of N-glycosylated asparagine residues from ER-localized proteins to aspartic acid has important implications for viral immunity. Many viral proteins are N-glycoyslated, including 22 such modifications on the Covid Spike protein, and our informatic analysis shows a strong signature of NGLY1-mediated protein editing for some Spike protein N-glycosylations. Viral immunity emerged in this past year as one of the major differences between the elderly and young adults: the death rate from Covid is 10x higher than the relative increase in death rate from any cause in over 65 year old adults compared to young adults. Thus a study of the molecular basis of viral immunity intersects the biology of aging. Our genetic analysis of how C. elegans surveils its mitochondria and other core cellular components for attacks to activate longevity programs as well as to innate immune and detoxification responses is a very non-standard view of innate immunity and aging. But the intersection with for example the use of rapamycin as an anti-aging drug is profound. We continue to focus on C. elegans in this proposal. Over the past five years, C. elegans classical genetic analysis, screening for mutant phenotypes and deducing the molecular defect that causes the phenotype by genome sequencing, has been transformed by low cost full genome sequencing of newly isolated mutants. All of the genes we propose to study have strong orthologues in humans, and are likely to function in humans in an ancient conserved pathway for detection of microbial assaults and control of the aging process by such surveillance. Variation in these same pathways will reveal how humans respond appropriately and inappropriately to drugs or bacterial pathogens, or activate drug detoxification pathways in the absence of a trigger. Such variation may also be the cause of diseases as diverse as anorexia nervosa, migraine, and autoimmunity, which, along with lifespan itself, are highly gender biased. Our proposal to study how the microbial flora attempt to subvert these pathways will also reveal how variation in the microbiome may underlie variation in human longevity.
