Genome-wide RNAi Screen for Fat Regulatory Genes in C. elegans Identifies a Proteostasis-AMPK Axis Critical for Starvation Survival.

Cell Rep
Authors
Keywords
Abstract

Organisms must execute metabolic defenses to survive nutrient deprivation. We performed a genome-wide RNAi screen in Caenorhabditis elegans to identify fat regulatory genes indispensable for starvation resistance. Here, we show that opposing proteostasis pathways are principal determinants of starvation survival. Reduced function of cytoplasmic aminoacyl tRNA synthetases (ARS genes) increases fat mass and extends starvation survival, whereas reduced proteasomal function reduces fat and starvation survival. These opposing pathways converge on AMP-activated protein kinase (AMPK) as the critical effector of starvation defenses. Extended starvation survival in ARS deficiency is dependent upon increased proteasome-mediated activation of AMPK. When the proteasome is inhibited, neither starvation nor ARS deficiency can fully activate AMPK, leading to greatly diminished starvation survival. Thus, activity of the proteasome and AMPK are mechanistically linked and highly correlated with starvation resistance. Conversely, aberrant activation of the proteostasis-AMPK axis during nutritional excess may have implications for obesity and cardiometabolic diseases.

Year of Publication
2017
Journal
Cell Rep
Volume
20
Issue
3
Pages
627-640
Date Published
2017 07 18
ISSN
2211-1247
DOI
10.1016/j.celrep.2017.06.068
PubMed ID
28723566
PubMed Central ID
PMC5578715
Links
Grant list
R01 DK101522 / DK / NIDDK NIH HHS / United States
P30 DK040561 / DK / NIDDK NIH HHS / United States
T32 DK007028 / DK / NIDDK NIH HHS / United States
P40 OD010440 / OD / NIH HHS / United States
K08 DK087941 / DK / NIDDK NIH HHS / United States
F32 DK103471 / DK / NIDDK NIH HHS / United States
R01 GM109028 / GM / NIGMS NIH HHS / United States
P30 DK057521 / DK / NIDDK NIH HHS / United States