Inactivation Of The Caenorhabditis Elegans Rnf-5 E3 Ligase Promotes Ire-1-Independent Er Functions

RNF5 is implicated in ERAD and in negative regulation of macroautophagy/autophagy. To better understand the function of RNF-5 under ER-stress conditions, we studied the ability ofCaenorhabditis elegans rnf-5(tm794)mutant animals to cope with stress in the background of impaired UPR machinery. We demonstrate that downregulation of RNF-5 decreased sensitivity to tunicamycin both in wild type and in anire-1 mutant. Double-mutantrnf-5;ire-1animals showed increased starvation resistance and extended lifespan when compared to theire-1 mutant. This partial rescue ofire-1required functional autophagy. Downregulation of RNF-5 rescued ER maturation defects and protein secretion of a DAF-28::GFP intestinal reporter in theire-1background. Proteomics and functional studies revealed an increase in lysosomal protease levels, in the frequency of intestinal lysosomes, and in lysosomal protease activity inrnf-5(tm794)animals. Together, these data suggest that RNF-5 is a negative regulator of ER stress, and that inactivation of RNF-5 promotes IRE-1-independent elevation of ER capacity.