A survival pathway for Caenorhabditis elegans with a blocked unfolded protein response.
The unfolded protein response (UPR) counteracts stress caused by unprocessed ER client proteins. A genome-wide survey showed impaired induction of many UPR target genes in xbp-1 mutant Caenorhabditis elegans that are unable to signal in the highly conserved IRE1-dependent UPR pathway. However a family of genes, abu (activated in blocked UPR), was induced to higher levels in ER-stressed xbp-1 mutant animals than in ER-stressed wild-type animals. RNA-mediated interference (RNAi) inactivation of a representative abu family member, abu-1 (AC3.3), activated the ER stress marker hsp-4::gfp in otherwise normal animals and killed 50% of ER-stressed ire-1 and xbp-1 mutant animals. Abu-1(RNAi) also enhanced the effect of inactivation of sel-1, an ER-associated protein degradation gene. The nine abu genes encode highly related type I transmembrane proteins whose lumenal domains have sequence similarity to a mammalian cell surface scavenger receptor of endothelial cells that binds chemically modified extracellular proteins and directs their lysosomal degradation. Our findings that ABU-1 is an intracellular protein located within the endomembrane system that is induced by ER stress in xbp-1 mutant animals suggest that ABU proteins may interact with abnormal ER client proteins and this function may be particularly important in animals with an impaired UPR.
Urano
Fumihiko
F
Skirball Institute, New York University School of Medicine, 540 First Avenue, New York, NY 10016, USA.
Calfon
Marcella
M
Yoneda
Takunari
T
Yun
Chi
C
Kiraly
Moni
M
Clark
Scott G
SG
Ron
David
D
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005656:Fungal Proteins / Q000378:metabolism*; D015801:Helminth Proteins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation; D017510:Protein Folding; D017346:Protein Serine-Threonine Kinases; D029701:Saccharomyces cerevisiae Proteins; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000502:physiology; D013534:Survival / Q000502:physiology
C466092:ABU-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D005656:Fungal Proteins; D015801:Helminth Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C101221:SEL-1 protein, C elegans; D029701:Saccharomyces cerevisiae Proteins; C082863:IRE1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases