The insulin/IGF signaling cascade modulates SUMOylation to regulate aging and proteostasis in Caenorhabditis elegans.

Lorna Moll,Yonatan B Tzur,Hana Boocholez,Filipa Carvalhal Marques,Tommer Ravid,Ehud Cohen,Atif Ahmed Siddiqui,Adi Biram,Hana Achache,Noa Roitenberg,Tayir Elami,Michal Bejerano-Sagie,Bar Lampert,Yuli Volovik,Danielle Grushko

doi:10.7554/elife.38635

Abstract

Although aging-regulating pathways were discovered a few decades ago, it is not entirely clear how their activities are orchestrated, to govern lifespan and proteostasis at the organismal level. Here, we utilized the nematode Caenorhabditis elegans to examine whether the alteration of aging, by reducing the activity of the Insulin/IGF signaling (IIS) cascade, affects protein SUMOylation. We found that IIS activity promotes the SUMOylation of the germline protein, CAR-1, thereby shortening lifespan and impairing proteostasis. In contrast, the expression of mutated CAR-1, that cannot be SUMOylated at residue 185, extends lifespan and enhances proteostasis. A mechanistic analysis indicated that CAR-1 mediates its aging-altering functions, at least partially, through the notch-like receptor glp-1. Our findings unveil a novel regulatory axis in which SUMOylation is utilized to integrate the aging-controlling functions of the IIS and of the germline and provide new insights into the roles of SUMOylation in the regulation of organismal aging.

Highlights

The view that aging is solely driven by stochastic events has changed as mounting evidences showed that certain, apparently independent, genetic and metabolic modulations, slow aging and extend lifespans of various organisms
Eggs of all worm strains were extracted from animals that were grown in 15 ̊C, and placed on plates that were seeded with either control bacteria, harboring the empty RNA interference (RNAi) vector (EV), or with daf-2 RNAi expressing bacteria
Knocking down daf-2 extends lifespan solely during reproductive adulthood (Dillin et al, 2002). This finding is interesting as other functions of the insulin/IGF signaling pathway (IIS) are regulated at other stages of the nematode’s lifecycle; egg laying is controlled during development (Dillin et al, 2002) and proteostasis is governed by the IIS during early and late adulthood (Cohen et al, 2010)

Summary

Introduction

The view that aging is solely driven by stochastic events has changed as mounting evidences showed that certain, apparently independent, genetic and metabolic modulations, slow aging and extend lifespans of various organisms. Reducing the activity of the IIS pathway slowed down aging in the worms It decreased the levels of SUMOylation of certain proteins, including CAR-1, which is found in the structures that produce germ cells. Replacing the protein with a mutated version of CAR-1 that cannot accept the SUMO element makes the worms live longer and resist a toxic protein that causes Alzheimer’s disease in humans These results show that, in C. elegans, the IIS pathway and a mechanism that involves CAR-1 in germ cells work together to determine the pace of aging. Despite the evidences that the ablation of germ cells extends lifespan (Hsin and Kenyon, 1999) and promotes proteostasis in C. elegans (Shemesh et al, 2013), it is unclear how the aging-regulating mechanisms downstream of the IIS and those that are activated by the reproduction system are linked, and whether posttranslational modifications play roles in the orchestration of these mechanisms. Our findings unveil a novel link between the reproductive system and the IIS, demonstrating that one downstream arm of this pathway regulates certain aspects of aging through the SUMOylation of CAR-1

Results

Discussion

Materials and methods

Funding Funder Israel Science Foundation