Transcriptional profiling of Caenorhabditis elegans nematodes bearing overexpression of NPP-16/CeNUP50 variants.

Deregulated nutrient sensing and metabolism are hallmarks of aging, whereas hormetic nutrient stress extends the lifespan and health span across species. As the only gateway governing nucleocytoplasmic trafficking, the nuclear pore complex (NPC) is critical for most fundamental cellular processes and becomes dysfunctional with age. However, the complexity of NPC composition and structure makes granular determination of the age-related role of specific nucleoporins challenging. Here we demonstrated that NUP50, a nuclear basket protein induced by AMP-activated protein kinase (AMPK) in a post-transcriptional and evolutionarily conserved way, is required for the metabolic rewiring and longevity of hormetic nutrient stress in Caenorhabditis elegans. Of interest, NUP50 sufficiently promotes transcriptomic alteration for lipid catabolism activation, extending lifespan independent of nuclear transport, but through its intrinsically disordered region (IDR) that binds to the promoter of catabolic genes. Our findings uncover a conserved nucleoporin as a metabolic switch bridging energy sensing, metabolic adaptation, and aging regulation by mediating transcription directly. Overall design: Wild-type (N2) animals and animals bearing integrated transgenic overexpression of full length NPP-16/CeNUP50 (MGH558) or NPP-16/CeNUP50 IDR deletion (MGH721) were bleach synchronized, plated on OP50-1 NGM agar plates, and collected at adult day 1 for total RNA extraction in biologically independent quadruplicates (12 total samples).