• Dorothé Jenni Eisermann, Uwe Wenzel, and Elena Fitzenberger.
• Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
• Biochem. Biophys. Res. Commun. 2016 May 13; 473 (4): 1052-1057.

AbstractThe 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.Copyright © 2016 Elsevier Inc. All rights reserved.

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