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Cochaperone Mzb1 is a key effector of Blimp1 in plasma cell differentiation and β1-integrin function

Virginia Andreani,Senthilkumar Ramamoorthy,Abhinav Pandey,Ekaterina Lupar,S. Nutt,T. Lämmermann,R. Grosschedl

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Antibody-secreting plasma cells are effectors of the humoral immune response. Transcription factor Blimp1 (Prdm1) is essential for the generation and function of plasma cells, and it regulates many genes, including Mzb1 (pERp1). Mzb1 protein is localized in the endoplasmic reticulum and acts as a cochaperone for the substrate-specific chaperone Grp94 (gp96). By the analysis of Mzb1−/−Prdm1+/gfp mice, we find that Mzb1 is required for T cell-independent immune responses and differentiation of plasma cells. In Mzb1−/−Prdm1+/gfp mice, we also observe impaired β1-integrin activation and trafficking of plasma cells to the bone marrow. Notably, we show that Mzb1 accounts for many of the Blimp1-associated downstream functions, suggesting that Mzb1 is a key effector of the Blimp1 regulatory network in plasma cells. Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 cochaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells. By analyzing Mzb1−/−Prdm1+/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of antibody-secreting cells in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes. In addition, we find that Mzb1−/− plasmablasts show a reduced activation of β1-integrin, which contributes to the impaired plasmablast differentiation and migration of antibody-secreting cells to the bone marrow. Thus, Mzb1 function is required for multiple aspects of plasma cell differentiation.

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