Lithocholic acid targets TULP3-Sirtuins to deacetylate v-ATPase and activate AMPK

ABSTRACT: Lithocholic acid (LCA), accumulated in mammals during calorie restriction (CR), can activate AMP-activated protein kinase (AMPK) and slow down ageing1. However, how LCA is signalled to activate AMPK and elicit the biological effects is unclear. Here, we show that LCA can enhance the activity of sirtuins (SIRTs) to deacetylate and subsequently inhibit vacuolar H+-ATPase (v-ATPase), thereby triggering AMPK activation via the lysosomal glucose-sensing pathway. Through proteomic analysis of SIRT1-coimmunoprecipitated proteins, we identify that TUB-like protein 3 (TULP3), a sirtuin-interacting protein2, is an LCA receptor, and demonstrate that the LCA-bound TULP3 allosterically activates SIRTs. Activated SIRTs then deacetylate the V1E1 subunit of v-ATPase on K52, K99 and K191 residues. Muscle-specific expression of the 3KR mutant of V1E1, mimicking the deacetylated state, dominantly activates AMPK and rejuvenates muscles in aged mice. Moreover, LCA depends on the TULP3 homologues tub-1 and ktub to activate AMPK and extend lifespan and healthspan in nematodes and flies, respectively. Our study thus elucidates that LCA triggers the TULP3-sirtuin-v-ATPase-AMPK route to manifest benefits of calorie restriction. This project contains the MS data for the modification of each of 21 v-ATPase subunits and the interacting protein of SIRT1 we identified. It also contains the validation data for MEF cell lines with bile acid receptor knockout.

ORGANISM(S): Homo Sapiens Mus Musculus

SUBMITTER: Shengcai Lin  

PROVIDER: PXD056134 | iProX | Mon Sep 16 00:00:00 BST 2024

REPOSITORIES: iProX