title: PEK-1 is crucial for hormesis induced by inhibition of the IRE-1/XBP-1 pathway in the Caenorhabditis elegans mev-1 mutant.
abstract: 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.
authors.affiliation: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
authors.forename: Dorothé Jenni
authors.initials: DJ
authors.lastname: Eisermann
authors.affiliation: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Wenzel
authors.affiliation: Molecular Nutrition Research, Interdisciplinary Research Center, Justus-Liebig-University of Giessen, Heinrich-Buff-Ring 26-32, D-35392 Giessen, Germany. Electronic address: elena.fitzenberger@ernaehrung.uni-giessen.de.
authors.forename: Elena
authors.initials: E
authors.lastname: Fitzenberger
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D045303:Cytochromes b; D059165:Hormesis / Q000502:physiology; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D019892:eIF-2 Kinase / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D045303:Cytochromes b; D017346:Protein Serine-Threonine Kinases; D013385:Succinate Dehydrogenase; D019892:eIF-2 Kinase; C472666:MEV-1 protein, C elegans; C548541:XBP-1 protein, C elegans; C541905:IRE-1 protein, C elegans
keywords: Caenorhabditis elegans; Hormesis; Proteasome; Proteostasis; Unfolded protein response