Bcl-x(L) Protein Protects from C/EBP Homologous Protein (CHOP)-dependent Apoptosis during Plasma Cell Differentiation

• Type of Material: Article
• Authors: Brian T. Gaudette, Emory University; Neal Iwakoshi, Emory University; Lawrence Boise, Emory University
• Language: English
• Date: 2014-08-22
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.M114.569376
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 289
• Issue: 34
• Start Page: 23629
• End Page: 23640
• Grant/Funding Information: This work was supported, in whole or in part, by National Institutes of Health Grants R01 CA127910 and R01 CA129968 as well as funding from the T. J. Martell Foundation (to L. H. B.).
• Keywords: KINASE; XBP-1; ATF6; MCL-1; Lymphocyte; UPR; B-CELLS; Science & Technology; Biochemistry & Molecular Biology; ER STRESS; ENDOPLASMIC-RETICULUM STRESS; Life Sciences & Biomedicine; ER Stress; Differentiation; MESSENGER-RNA; Plasma Cell; TRANSCRIPTION FACTORS; Apoptosis; DEATH; Bcl-2 Proteins

Abstract

Although it is known that the unfolded protein response (UPR) plays a significant role in the process of plasma cell differentiation, the contribution of the individual sensors of the UPR to this process remains unclear. In this study we examine the death signals and compensatory survival signals activated during B cell activation and the first stages of plasma cell differentiation. During in vitro differentiation of both primary murine B cells and the Bcl1 cell line, we demonstrate that in addition to activation of the physiological UPR, changes in the expression of several Bcl-2 proteins occur, which are consistent with a lowering of the apoptotic threshold of the cell. Specifically, we observed decreased expression of Bcl-2 and Mcl-1 and increased expression of the proapoptotic protein Bim. However, these changes were countered by Bcl-x L induction, which is necessary to protect differentiating cells both from ER stress-induced death by tunicamycin and from the death signals inherent in differentiation. Consistent with differentiating cells becoming dependent on Bcl-xL for survival, the addition of ABT-737 resulted in apoptosis in differentiating cells through the inhibition of sequestration of Bim. Confirming this result, differentiation in the context of RNAi-mediated Bcl-xL knockdown also induced apoptosis. This cell death is C/EBP homologous protein (CHOP)-dependent, connecting these events to the UPR. Thus plasma cell differentiation proceeds through a Bcl-xL-dependent intermediate.