title: The KDEL receptor modulates the endoplasmic reticulum stress response through mitogen-activated protein kinase signaling cascades.
abstract: The accumulation of misfolded proteins in the endoplasmic reticulum (ER) evokes the ER stress response. The resultant outcomes are cytoprotective but also proapoptotic. ER chaperones and misfolded proteins exit to the secretory pathway and are retrieved to the ER, during which process the KDEL receptor plays a significant role. Using an expression of a mutant KDEL receptor that lacks the ability for ligand recognition, we show that the impairment of retrieval by the KDEL receptor led to a mis-sorting of the immunoglobulin-binding protein BiP, an ER chaperone that has a retrieval signal from the early secretory pathway, which induced intense ER stress response and an increase in susceptibility to ER stress in HeLa cells. Furthermore, we show that the ER stress response accompanied the activation of p38 mitogen-activated protein (MAP) kinases and c-Jun amino-terminal kinases (JNKs) and that the expression of the mutant KDEL receptor suppressed the activation of p38 and JNK1 but not JNK2. The effect of the expression of the mutant KDEL receptor was consistent with the effect of a specific inhibitor for p38 MAP kinases, because the inhibitor sensitized HeLa cells to ER stress. We also found that activation of the KDEL receptor by the ligand induced the phosphorylation of p38 MAP kinases. These results indicate that the KDEL receptor participates in the ER stress response not only by its retrieval ability but also by modulating MAP kinase signaling, which may affect the outcomes of the mammalian ER stress response.
authors.affiliation: Department of Molecular Embryology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan.
authors.forename: Katsushi
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Hamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shinkai
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Kohno
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Koseki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Aoe
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006367:HeLa Cells; D006360:Heat-Shock Proteins; D006801:Humans; D007136:Immunoglobulins / Q000737:chemistry; D048031:JNK Mitogen-Activated Protein Kinases; D008024:Ligands; D020935:MAP Kinase Signaling System; D048055:Mitogen-Activated Protein Kinase 8; D048056:Mitogen-Activated Protein Kinase 9; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D017510:Protein Folding; D018000:Receptors, Peptide / Q000737:chemistry*; D015398:Signal Transduction; D013312:Stress, Physiological; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases
chemical_list: D002352:Carrier Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007136:Immunoglobulins; C064459:KDEL receptor; D008024:Ligands; D018832:Molecular Chaperones; D018000:Receptors, Peptide; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases