A dicer-related helicase opposes the age-related pathology from SKN-1 activation in ASI neurons

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 120; no. 52; p. e2308565120
• Main Authors: Turner, Chris D, Stuhr, Nicole L, Ramos, Carmen M, Van Camp, Bennett T, Curran, Sean P
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 26.12.2023
• Subjects: Aging; Animals; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - metabolism; Cellular stress response; Circuits; DNA helicase; DNA-Binding Proteins - metabolism; Gene expression; Homeostasis; Intestine; Life span; Lipid metabolism; Lipids; Longevity - genetics; Nervous system; Neurons; Neurons - metabolism; Oxidative Stress - physiology; Ribonucleic acid; RNA; RNA-mediated interference; Transcription activation; Transcription Factors - metabolism; ASI neurons; C. elegans; aging; cell nonautonomous signaling; transcriptional capacity
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2308565120

Coordination of cellular responses to stress is essential for health across the lifespan. The transcription factor SKN-1 is an essential homeostat that mediates survival in stress-inducing environments and cellular dysfunction, but constitutive activation of SKN-1 drives premature aging thus revealing the importance of turning off cytoprotective pathways. Here, we identify how SKN-1 activation in two ciliated ASI neurons in results in an increase in organismal transcriptional capacity that drives pleiotropic outcomes in peripheral tissues. An increase in the expression of established SKN-1 stress response and lipid metabolism gene classes of RNA in the ASI neurons, in addition to the increased expression of several classes of noncoding RNA, define a molecular signature of animals with constitutive SKN-1 activation and diminished healthspan. We reveal neddylation as a unique regulator of the SKN-1 homeostat that mediates SKN-1 abundance within intestinal cells. Moreover, RNAi-independent activity of the dicer-related DExD/H-box helicase, , in the intestine, can oppose the effects of aberrant SKN-1 transcriptional activation and delays age-dependent decline in health. Taken together, our results uncover a cell nonautonomous circuit to maintain organism-level homeostasis in response to excessive SKN-1 transcriptional activity in the sensory nervous system.