Protein degradation mechanisms are integral for the preservation of the proteome. Their reduced efficiency during aging leads to protein misfolding and aggregation which potentiate several proteotoxic disorders. Paradoxically, our lab reported that the Caenorhabditis elegans
rpn-10(
ok1865) proteasome mutant exhibits enhanced proteostasis, elevated stress resistance and extended lifespan. The RPN-10/PSMD4 subunit is a 19S regulatory particle (RP) ubiquitin receptor of the 26S proteasome that targets polyubiquitinated soluble substrates to its 20S catalytic core for degradation. Notably, the proteasome dysfunction of the
rpn-10 mutant is characterized by reduced, not inhibited, ubiquitin fusion degradation (UFD). We ascertained that the compensatory upregulation of autophagy and SKN-1/Nrf-mediated responses partially contribute to the robust
rpn-10 mutant phenotype. To elucidate the suite of protective mechanisms, our RNA-sequencing data analysis revealed that several ERQC genes are transcriptionally upregulated in the
rpn-10 mutant. Thus, we hypothesized that the
rpn-10 mutant exhibits enhanced ER proteostasis which mediates its superior cellular stress resistance. Accordingly, the
rpn-10 mutant exhibits higher ER stress resistance and altered ER homeostasis compared to the wild-type. Complementarily, the attenuated expression of the aggregation-prone mutant ?-1 antitrypsin (ATZ) reporter proves that ER proteostasis is also ameliorated in the
rpn-10 mutant. Via a forward genetics screen for suppressors of decreased ATZ aggregation in the
rpn-10 mutant, we identified a novel player, H04D03.3, which is a putative homolog of the proteasome-associated adaptor protein ECM29. This finding unexpectedly suggests that the assembly of the
rpn-10 mutant proteasome itself distinctly regulates its ER proteostasis. Moreover, we observed that the cytosolic proteostasis and longevity benefits are contingent on the ER master chaperone
hsp-3/-4 (BiP) and ER ATPase
cdc-48.2 (
p97/VCP), thus profoundly highlighting the significance of ERQC in the
rpn-10 mutant. Altogether, it appears that mild proteasomal dysfunction induces a unique ERQC adaptation that underlies improved proteostasis and increased longevity of the
rpn-10 mutant.