title: MZB1 is a GRP94 cochaperone that enables proper immunoglobulin heavy chain biosynthesis upon ER stress.
abstract: MZB1 (pERp1) is a B-cell-specific and endoplasmic reticulum (ER)-localized protein implicated in antibody secretion and integrin-mediated cell adhesion. Here, we examine the role of MZB1 in vivo by conditional gene inactivation in the mouse germline and at different stages of B lymphopoiesis. Deletion of MZB1 impairs humoral immune responses and antibody secretion in plasma cells that naturally undergo ER stress. In addition, we found that experimental induction of ER stress by tunicamycin injections in mice results in a block of pro-B-cell to pre-B-cell differentiation specifically in Mzb1(-/-) mice. A similar developmental block was observed in Mzb1(fl/fl)mb1(Cre) mice, whereby a Cre recombinase-induced genotoxic stress unmasks a role for MZB1 in the surface expression of immunoglobulin µ heavy chains (µHCs). MZB1 associates directly with the substrate-specific chaperone GRP94 (also called HSP90B1 or gp96) in an ATP-sensitive manner and is required for the interaction of GRP94 with µHCs upon ER stress. Thus, MZB1 seems to act as a substrate-specific cochaperone of GRP94 that enables proper biosynthesis of µHCs under conditions of ER stress.
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Rosenbaum
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Virginia
authors.initials: V
authors.lastname: Andreani
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Tanya
authors.initials: T
authors.lastname: Kapoor
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Herp
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Henrik
authors.initials: H
authors.lastname: Flach
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Marlena
authors.initials: M
authors.lastname: Duchniewicz
authors.affiliation: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg 79108, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Grosschedl
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D055786:Gene Knockout Techniques; D056724:Immunity, Humoral / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000096:biosynthesis* / Q000235:genetics; D007148:Immunoglobulin mu-Chains / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism*
chemical_list: D007143:Immunoglobulin Heavy Chains; D007148:Immunoglobulin mu-Chains; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C053387:endoplasmin; C546362:pERp1 protein, mouse
keywords: B lymphopoiesis; ER stress; GRP94; MZB1; antibody secretion; cochaperone