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J. Biol. Chem., Vol. 283, Issue 26, 17954-17961, June 27, 2008

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B- and T-cell Development Both Involve Activity of the Unfolded Protein Response Pathway^*

Ryan Brunsing, Sidne A. Omori, Frank Weber¹, Alicia Bicknell, Leslie Friend, Robert Rickert, and Maho Niwa²

From the Division of Biological Sciences, Section of Molecular Biology, University of California, San Diego, La Jolla, California, 92093-0377 and The Burnham Institute, La Jolla, California 92037

The unfolded protein response (UPR) signaling pathway regulates the functional capacity of the endoplasmic reticulum for protein folding. Beyond a role for UPR signaling during terminal differentiation of mature B cells to antibody-secreting plasma cells, the status or importance of UPR signaling during hematopoiesis has not been explored, due in part to difficulties in isolating sufficient quantities of cells at developmentally intermediate stages required for biochemical analysis. Following reconstitution of irradiated mice with hematopoietic cells carrying a fluorescent UPR reporter construct, we found that IRE1 nuclease activity for XBP1 splicing is active at early stages of T- and B-lymphocyte differentiation: in bone marrow pro-B cells and in CD4⁺CD8⁺ double positive thymic T cells. IRE1 was not active in B cells at later stages. In T cells, IRE activity was not detected in the more mature CD4⁺ T-cell population but was active in the CD8⁺ cytotoxic T-cell population. Multiple signals are likely to be involved in activating IRE1 during lymphocyte differentiation, including rearrangement of antigen receptor genes. Our results show that reporter-transduced hematopoietic stem cells provide a quick and easy means to identify UPR signaling component activation in physiological settings.

Received for publication, February 21, 2008

^* This work was supported by the Searle Scholar Program (to M. N.) via the University of California Cancer Research Committee and by American Cancer Society Grant RSG-05-059-01-GMC (to M. N.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ Present address: Biochemie-Zentrum Heidelberg, Universität Heidelberg, Im Neuenheimer Feld 328, 69120 Heidelberg, Germany.

² To whom correspondence should be addressed. Tel.: 858-822-3451; Fax: 858-822-0317; E-mail: niwa{at}ucsd.edu.

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