Inactivation of the <i>Caenorhabditis elegans</i> 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 of <i>Caenorhabditis elegans rnf-5(tm794)</i> 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 an <i>ire-1</i> mutant. Double-mutant <i>rnf-5;ire-1</i> animals showed increased starvation resistance and extended lifespan when compared to the <i>ire-1</i> mutant. This partial rescue of <i>ire-1</i> required functional autophagy. Downregulation of RNF-5 rescued ER maturation defects and protein secretion of a DAF-28::GFP intestinal reporter in the <i>ire-1</i> background. Proteomics and functional studies revealed an increase in lysosomal protease levels, in the frequency of intestinal lysosomes, and in lysosomal protease activity in <i>rnf-5(tm794)</i> 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.