title: Cab45S inhibits the ER stress-induced IRE1-JNK pathway and apoptosis via GRP78/BiP.
abstract: Disturbance of endoplasmic reticulum (ER) homeostasis causes ER stress and leads to activation of the unfolded protein response, which reduces the stress and promotes cell survival at the early stage of stress, or triggers cell death and apoptosis when homeostasis is not restored under prolonged ER stress. Here, we report that Cab45S, a member of the CREC family, inhibits ER stress-induced apoptosis. Depletion of Cab45S increases inositol-requiring kinase 1 (IRE1) activity, thus producing more spliced forms of X-box-binding protein 1 mRNA at the early stage of stress and leads to phosphorylation of c-Jun N-terminal kinase, which finally induces apoptosis. Furthermore, we find that Cab45S specifically interacts with 78-kDa glucose-regulated protein/immunoglobulin heavy chain binding protein (GRP78/BiP) on its nucleotide-binding domain. Cab45S enhances GRP78/BiP protein level and stabilizes the interaction of GRP78/BiP with IRE1 to inhibit ER stress-induced IRE1 activation and apoptosis. Together, Cab45S, a novel regulator of GRP78/BiP, suppresses ER stress-induced IRE1 activation and apoptosis by binding to and elevating GRP78/BiP, and has a role in the inhibition of ER stress-induced apoptosis.
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
authors.forename: S
authors.initials: S
authors.lastname: Xu
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
authors.forename: X
authors.initials: X
authors.lastname: Wen
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.affiliation: 1] Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China [2] Center for Quantitative Biology, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key Laboratory of Cell Proliferation and Differentiation of the Ministry of Education, State Key Laboratory of Bio-membrane and Membrane Bio-engineering, College of Life Sciences, Peking University, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Teng
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019556:COS Cells; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D020033:Protein Isoforms; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D034622:RNA Interference; D015398:Signal Transduction; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006023:Glycoproteins; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D020033:Protein Isoforms; D014415:Tunicamycin; C099100:SDF4 protein, human; D019284:Thapsigargin; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D004722:Endoribonucleases