The accumulation of unfolded proteins in the endoplasmic reticulum (ER) causes an imbalance of proteostasis and is related to many pathological conditions. In answer to this ER stress cells activate a network of three integrated signaling pathways consolidated as the unfolded protein response of the ER (UPR(ER)), which is also present in the stress-sensitive Caenorhabditis elegans mutant
mev-1. Whereas inhibition of one of those pathways by RNA-interference (RNAi) versus
xbp-1 results in reduced survival of
mev-1 nematodes under heat stress, additional knockdown of the
xbp-1 splicing activator
ire-1 results in a PEK-1-dependent hormetic response. In contrast, increased survival under
ire-1/xbp-1 double RNAi was found to be independent of the presence of HSP-4, an UPR(ER)-specific chaperone, as evidenced under
ire-1/xbp-1/hsp-4 triple knockdown conditions. Moreover,
ire-1/xbp-1 double-RNAi significantly increased chymotrypsin-like proteasomal activity, which was completely blocked under additional RNAi versus
pek-1. In conclusion, we identified PEK-1 as a mediator of hormesis in the
mev-1 mutant of C. elegans which is induced by simultaneous inhibition of XBP-1 and its splicing activator IRE-1 and mediated through activation of the proteasome.