Researchers here find that one of the protein components of nuclear pore structures has an independent function in regulating the response to nutrient sensing. As is now well known, low nutrient availability resulting from reduced calorie intake triggers a range of adaptive responses that collectively act to slow the progression of aging. Evidence suggests that increased autophagy is the most vital of these mechanisms, but it is far from the only mechanism involved. Thus interventions such as mTOR inhibitors that increase autophagy are beneficial, but not as beneficial as calorie restriction.
The nuclear pore complex (NPC) is a massive protein complex that is best known for its role in gating communication between the cell cytosol and nucleus. The NPC consists of about 30 different proteins, known as nucleoporins, as a heteromultimeric assembly of more than 1000 protein subunits that mediate nuclear pore permeability, active transport, and on-site transcription.
In this study, we demonstrate that the NPC subunit NPP-16/NUP50 bridges energy sensing and metabolic adaptation independently of its canonical role in nuclear permeability and transport. In response to energetic and nutrient stress, NPP-16/NUP50 is post-translationally activated by AMPK, and subsequently promotes the transcription of lipid catabolic genes. Overexpression of NPP-16/NUP50 is sufficient to induce lipid catabolism in both nematodes and mammalian cells. NPP-16/NUP50 overexpression robustly extends the lifespan in C. elegans by enhancing the transcriptional activity of the metabolic transcriptional regulators NHR-49/HNF4 and HLH-30/TFEB, driving lipid catabolism.
Unlike scaffold nucleoporins, altered levels or activity of NPP-16/NUP50 do not affect nuclear transport and permeability; instead, increased NPP-16/NUP50 levels are necessary and sufficient to promote metabolic adaptation and longevity via interaction of its intrinsically disordered region (IDR) with the promoters of lipid catabolic genes. Our findings identify a heretofore unappreciated, conserved role of a specific nucleoporin in energy sensing and deployment of metabolic stress defenses against aging and further uncover a noncanonical role for nucleoporin IDRs in direct transcriptional regulation.
Link: https://doi.org/10.1101/2025.02.17.638704
View the full article at FightAging
