GTPase-mediated regulation of the unfolded protein response in Caenorhabditis elegans is dependent on the AAA+ ATPase CDC-48.
When endoplasmic reticulum (ER) homeostasis is perturbed, an adaptive mechanism is triggered and named the unfolded protein response (UPR). Thus far, three known UPR signaling branches (IRE-1, PERK, and ATF-6) mediate the reestablishment of ER functions but can also lead to apoptosis if ER stress is not alleviated. However, the understanding of the molecular mechanisms integrating the UPR to other ER functions, such as membrane traffic or endomembrane signaling, remains incomplete. We consequently sought to identify new regulators of UPR-dependent transcriptional mechanisms and focused on a family of proteins known to mediate, among other, ER-related functions: the small GTP-binding proteins of the RAS superfamily. To this end, we used transgenic UPR reporter Caenorhabditis elegans strains as a model to specifically silence small-GTPase expression. We show that the Rho subfamily member CRP-1 is an essential component of UPR-induced transcriptional events through its physical and genetic interactions with the AAA+ ATPase CDC-48. In addition, we describe a novel signaling module involving CRP-1 and CDC-48 which may directly link the UPR to DNA remodeling and transcription control.
Caruso
Marie-Elaine
ME
Team Avenir, INSERM U889, Université Bordeaux 2, 146 rue Léo Saignat, 33076 Bordeaux, France.
Jenna
Sarah
S
Bouchecareilh
Marion
M
Baillie
David L
DL
Boismenu
Daniel
D
Halawani
Dalia
D
Latterich
Martin
M
Chevet
Eric
E
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004229:Dithiothreitol / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D046912:Multiprotein Complexes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D017510:Protein Folding; D019284:Thapsigargin / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014415:Tunicamycin / Q000494:pharmacology; D000074405:Valosin Containing Protein; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D046912:Multiprotein Complexes; D014415:Tunicamycin; D049452:Green Fluorescent Proteins; D001383:Azetidinecarboxylic Acid; D019284:Thapsigargin; D000251:Adenosine Triphosphatases; C502924:CRP-1 protein, C elegans; D020558:GTP Phosphohydrolases; D000074405:Valosin Containing Protein; D020741:rho GTP-Binding Proteins; D004229:Dithiothreitol