The loss of proteostasis due to reduced efficiency of protein degradation pathways has been highlighted in several aging processes and age-related disorders. Paradoxically, we have reported that the Caenorhabditis elegans
rpn-10(
ok1865) proteasomal subunit mutant exhibits enhanced proteostasis, elevated stress resistance and extended lifespan. The RPN-10/PSMD4 subunit is a ubiquitin receptor on the 26S proteasome that targets polyubiquitinated substrates to its catalytic core for degradation. The
rpn-10 mutant possesses mild proteasome dysfunction and a distinct proteasomal peptidase activity profile. Notably, compensatory activation of autophagy and SKN-1/Nrf-regulated responses only partially underlie the robust
rpn-10 mutant phenotype, thus prompting our further investigation into its novel protective processes. To this end, we observed that several endoplasmic reticulum protein quality control (ERQC) genes were transcriptionally upregulated in the
rpn-10 mutant. This is functionally relevant in the
rpn-10 mutant which exhibits higher ER stress resistance and altered ER homeostasis compared to the wild-type. Moreover, as a significant subset of the upregulated ERQC genes was enriched for ER-associated proteasome-mediated degradation (ERAD), we sought to determine the turnover of ER substrates in the
rpn-10 mutant. As expected, the attenuated accumulation of the ER-localized aggregation-prone mutant alpha-1 antitrypsin (ATZ) reporter indicated that ER proteostasis is augmented in the
rpn-10 mutant. Via a forward genetics screen for suppressors of decreased ATZ aggregation in the
rpn-10 mutant, we identified an unexpected player,
ecps-2, which is a homolog of the proteasome-associated adaptor protein ECM29. While we observed that
ecps-2 did not regulate proteasomal subunit expression or the ER stress response, we found that the loss of
ecps-2 in the
rpn-10 mutant strongly reduces its proteasomal chymotrypsin-like activity. Altogether, this suggests that the modified proteasomal assembly of the
rpn-10 mutant contributes to its cellular proteostasis. Furthermore, the increased
rpn-10 mutant lifespan appears to depend partially on
ecps-2 but more strongly on its ERQC status. Therefore, we propose that the
ecps-2-proteasome interaction induces a unique ERQC adaptation which supports the superior proteostasis and longevity of the
rpn-10 mutant.