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J. Biol. Chem., Vol. 280, Issue 48, 39762-39771, December 2, 2005

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

Alison H. Skalet1, Jennifer A. Isler2, Leslie B. King, Heather P. Harding¶, David Ron¶, and John G. Monroe3

From the Department of Pathology and Laboratory Medicine and Department of Cancer Biology and Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104 and the ^¶Skirball Institute of Biomolecular Medicine, Department of Medicine, New York University School of Medicine, New York, New York 10016

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.

Received for publication, March 10, 2005 , and in revised form, July 1, 2005.

^* This work was supported by National Institutes of Health Grants AI 32592 and AI 43620 (to J. G. M.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Supported by a Howard Hughes Medical Institute predoctoral fellowship.

² Supported by National Institutes of Health F32 AI062055 [GenBank] -01.

³ To whom correspondence should be addressed: 311 Biomedical Research Bldg. II/III, 421 Curie Blvd., University of Pennsylvania School of Medicine, Philadelphia, PA 19104. Tel.: 215-898-2873; Fax: 215-573-2014; E-mail: monroej{at}mail.med.upenn.edu.

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