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 mb1Cre mice, whereby a Cre recombinase-induced genotoxic stress unmasks a role for MZB1 in the surface expression of immunoglobulin m heavy chains (mHCs). 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 mHCs upon ER stress. Thus, MZB1 seems to act as a substrate-specific cochaperone of GRP94 that enables proper biosynthesis of mHCs under conditions of ER stress.

Gene‐Expression Profiles in Generalized Aggressive Periodontitis: A Gene Network‐Based Microarray Analysis

“…Scientists from the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE) have now shown that the protein MZB1 has a stress-reducing effect on the cell. 28 The protein apparently helps newly-forming antibodies to adopt their correct structure. Studies indicate that there are dramatic differences in MZB1 gene expressions between the chronic and aggressive periodontitis patients.…”

Interaction of CCR4–NOT with EBF1 regulates gene-specific transcription and mRNA stability in B lymphopoiesis

“…In particular, the expression of the Ig surrogate light chain genes VpreB and Igll1 (encoding λ5) is down-regulated in EBF1H240A-expressing cells relative to EBF1wt-expressing cells. In addition, we observed a reduced expression of Rag1, Pou2af1 (encoding OcaB), and Mzb1, encoding an ER-resident cochaperone that influences the folding of the Ig µ heavy chain and helps to buffer the effects of DNA damage in early B-lineage cells (Rosenbaum et al 2014). In support of a role of the interaction of the CCR4-NOT complex with EBF1, we observed a similar developmental block in Cnot3 fl/fl RERT Cre mice in which the second and third exons were deleted upon tamoxifen treatment.…”

“…Therefore, we suggest that the effect of Cnot3 deficiency on Igh recombination is indirect via a reduced autoregulation of Ebf1 and reduced expression of Pax5. Moreover, the altered expression of p53 is not observed in Cnot3 fl/fl RERT Cre mice and may be linked to the genotoxic stress observed in pro-B cells of the mb1 Cre mouse line (Rosenbaum et al 2014). …”

“…A block of pro-B-to-pre-B-cell differentiation was observed only in the presence of the mb1 Cre allele, which induces genotoxic stress via abundant Cre accumulation in the nucleus because of optimized codon usage and the presence of a nuclear localization sequence (Hobeika et al 2006;Rosenbaum et al 2014). The Mzb1 gene is bound and differentially regulated by EBF1wt and EBF1H240A and is modestly but significantly down-regulated in Cnot3 knockout pro-B cells ( Fig.…”

“…The phenotypic differences of Cnot3 fl/fl RERT Cre and Cnot3 fl/fl mb1 Cre mice reminded us of differences in the block of pro-B-to-pre-B-cell differentiation in mice carrying a germline-null mutation of the Mzb1 gene versus mice containing a floxed Mzb1 allele in combination with the mb1 Cre allele (Rosenbaum et al 2014). A block of pro-B-to-pre-B-cell differentiation was observed only in the presence of the mb1 Cre allele, which induces genotoxic stress via abundant Cre accumulation in the nucleus because of optimized codon usage and the presence of a nuclear localization sequence (Hobeika et al 2006;Rosenbaum et al 2014).…”