Endoplasmic reticulum HSP90b1 (gp96, grp94) optimizes B-cell function via chaperoning integrin and TLR but not immunoglobulin.
Endoplasmic reticulum (ER) unfolded protein response (UPR) plays pivotal roles in both early B-cell development and plasma cell differentiation. As a major ER chaperone to mediate the UPR and a master chaperone for Toll-like receptors (TLRs), HSP90b1 (grp94, gp96) has long been implicated to facilitate the assembly of immunoglobulin. We hereby critically and comprehensively examine the roles of HSP90b1 in B-cell biology in vivo using B-cell-specific HSP90b1-null mice. We found that knockout B cells developed normally. There were no apparent problems with plasma cell differentiation, Ig assembly, class-switching, and Ig production. Strikingly, although both mutant conventional and innatelike B cells failed to compartmentalize properly due to loss of select but not all integrins, HSP90b1 was required for neither germinal center formation nor memory antibody responses in vivo. The only significant defect associated with HSP90b1 ablation in B cells was an attenuated antibody production in the context of TLR stimulation. Thus, our study has resolved the long-standing question regarding HSP90b1 in B-cell biology: HSP90b1 optimizes the function of B cells by chaperoning TLRs and integrins but not immunoglobulin. This study also has important implications in resolving the controversial roles of TLR in B-cell biology.
Department of Immunology, Center for Immunotherapy of Cancer and Infectious Diseases, Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030-1601, USA.
Bei
B
Liu
Zihai
Z
Li
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002634:Chemotaxis, Leukocyte; D004721:Endoplasmic Reticulum / Q000737:chemistry*; D018858:Germinal Center; D018841:HSP90 Heat-Shock Proteins / Q000502:physiology; D007136:Immunoglobulins / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D018832:Molecular Chaperones / Q000378:metabolism; D021381:Protein Transport; D051193:Toll-Like Receptors / Q000378:metabolism*
D018841:HSP90 Heat-Shock Proteins; D007136:Immunoglobulins; D016023:Integrins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; D051193:Toll-Like Receptors; C053387:endoplasmin