TORC1-mediated sensing of chaperone activity alters glucose metabolism and extends lifespan.

Matea Perić,Sandra Sobočanec,Marina Rudan,Nuno Raimundo,Sven Dennerlein,Anita Kriško,Andrea Nikolić,Ana‐Matea Mikecin,Ira Milošević,Anita Lovrić,Peter Bou Dib,Kristian Vlahoviček,Marina Musa,Ana Šarić

doi:10.1111/acel.12623

Abstract

SummaryProtein quality control mechanisms, required for normal cellular functioning, encompass multiple functions related to protein production and maintenance. However, the existence of communication between proteostasis and metabolic networks and its underlying mechanisms remain elusive. Here, we report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82. Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability. This mechanism culminates in the extension of yeast replicative lifespan (RLS) that is fully reliant on both TORC1 deactivation and Snf1/AMPK activation. Specifically, we identify oxygen consumption increase as the downstream effect of Snf1 activation responsible for the entire RLS extension. Our results set a novel paradigm for the role of proteostasis in aging: modulation of the misfolded protein level can affect cellular metabolic features as well as mitochondrial activity and consequently modify lifespan. The described mechanism is expected to open new avenues for research of aging and age‐related diseases.

Highlights

Protein homeostasis encompasses the equilibrium between synthesis, conformational maintenance, and degradation of damaged proteins
We report that enhanced chaperone activity and consequent improved proteostasis are sensed by TORC1 via the activity of Hsp82
Chaperone enrichment decreases the level of Hsp82, which deactivates TORC1 and leads to activation of Snf1/AMPK, regardless of glucose availability

Summary

Introduction

Protein homeostasis (proteostasis) encompasses the equilibrium between synthesis, conformational maintenance, and degradation of damaged proteins. Cellular proteostasis is maintained by a network of molecular chaperones, protein degradation machineries, and stress–response pathways, whose coordinated action senses and counteracts protein misfolding (Wolff et al, 2014). Molecular chaperones, including the heat-shock proteins (HSPs), are ubiquitously present cellular proteins, which display a wide spectrum of folding-oriented activities, coping with regular protein folding events, as well as stressinduced protein misfolding (Morano et al, 1998). As a result of such a decline, proteins cannot maintain their native fold or perform their function and, cells promote the removal of damaged proteins through their degradation, refolding, and/ or aggregation (Brandvold & Morimoto, 2015). The cell-wide response to the enrichment in chaperone activity has not received any attention

Results

Discussion

Conclusion