Megaprotein brakes for insulin-mTOR and aging
Insulin-mTOR signals drive anabolic growth during organismal development. However, its late-life antagonistic pléiotropy compromises lifespan in animals of all phylogenetic groups. LPD-3 is identified as the megaprotein that controls insulin-mTOR signaling in C. elegans. In lpd-3 mutations, we find that a C.elegans model for human Alkuraya – Kuciniskas syndrome, an agonist insulin called INS-7 is produced in excess and reduces lifespan. LPD-3 forms a tunnel-like bridge megaprotein that facilitates phospholipid transport to the plasma membrane. Lipidomic profile analysis reveals an increased abundance of hexaceramides in lpd-3 mutations. This is accompanied by the up-regulation hexaceramide synthesizing enzymes including HYL-1. Reduced HYL-1 levels decrease INS-7 and restore the shortened lifespan in lpd-3 mutations via insulin receptor/DAF-2, mTOR/LET-363 and reducing HYL-1. LPD-3 reduces the abundance of proteins in wild-type animals as it antagonizes SINH-1. We propose that LPD-3 acts as a megaprotein brake for aging and its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
The authors have not declared any competing interests.
Source:
https://www.biorxiv.org/content/10.1101/2023.02.14.528431v2?ct
