Rapid B Cell Receptor-induced Unfolded Protein Response in Nonsecretory B Cells Correlates with Pro- Versus Antiapoptotic Cell Fate

• Published in: The Journal of biological chemistry Vol. 280; no. 48; pp. 39762 - 39771
• Main Authors: Skalet, Alison H., Isler, Jennifer A., King, Leslie B., Harding, Heather P., Ron, David, Monroe, John G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02.12.2005; American Society for Biochemistry and Molecular Biology
• Subjects: Alleles; Animals; Apoptosis; B-Lymphocytes - cytology; B-Lymphocytes - metabolism; Blotting, Western; CD40 Antigens - biosynthesis; Cell Differentiation; Cell Lineage; Cell Membrane - metabolism; Cytoplasm - metabolism; Endoplasmic Reticulum - metabolism; Exons; Genes, Reporter; Immunoglobulins - metabolism; Lipopolysaccharides - chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Microscopy, Electron; Mutation; Protein Denaturation; Protein Folding; Receptors, Antigen, B-Cell - metabolism; Receptors, Interleukin-4 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction; Time Factors; Toll-Like Receptor 4 - metabolism; Transcription Factor CHOP - metabolism; Up-Regulation
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M502640200

The adaptive unfolded protein response (UPR) is essential for the development of antibody-secreting plasma cells. B cells induced by lipopolysaccharide (LPS) to differentiate into plasma cells exhibit a nonclassical UPR reported to anticipate endoplasmic reticulum stress prior to immunoglobulin production. Here we demonstrate that activation of a physiologic UPR is not limited to cells undergoing secretory cell differentiation. We identify B cell receptor (BCR) signaling as an unexpected physiologic UPR trigger and demonstrate that in mature B cells, BCR stimulation induces a short lived UPR similar to the LPS-triggered nonclassical UPR. However, unlike LPS, BCR stimulation does not induce plasma cell differentiation. Furthermore, the BCR-induced UPR is not limited to cells in which BCR induces activation, since a UPR is also induced in transitional immature B cells that respond to BCR stimulation with a rapid apoptotic fate. This response involves sustained up-regulation of Chop mRNA indicative of a terminal UPR. Whereas sustained Chop expression correlates with the ultimate fate of the BCR-triggered B cell and not its developmental stage, Chop–/– B cells undergo apoptosis, indicating that CHOP is not required for this process. These studies establish a system whereby a terminal or adaptive UPR can be alternatively triggered by physiologic stimuli.