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* Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN 38105; and
Department of Molecular Sciences, University of Tennessee, Health Science Center, Memphis, TN 38163
Plasma cell differentiation is accompanied by a modified unfolded protein response (UPR), which involves activation of the Ire1 and activating transcription factor 6 branches, but not the PKR-like endoplasmic reticulum kinase branch. Ire1-mediated splicing of XBP-1 (XBP-1(S)) is required for terminal differentiation, although the direct targets of XBP-1(S) in this process have not been identified. We demonstrate that XBP-1(S) binds to the promoter of ERdj3 in plasmacytoma cells and in LPS-stimulated primary splenic B cells, which corresponds to increased expression of ERdj3 transcripts in both cases. When small hairpin RNA was used to decrease XBP-1 expression in plasmacytoma lines, ERdj3 transcripts were concomitantly reduced. The accumulation of Ig 
H chain protein was also diminished, but unexpectedly this occurred at the transcriptional level as opposed to effects on H chain stability. The decrease in H chain transcripts correlated with a reduction in mRNA encoding the H chain transcription factor, OBF-1/BOB-1/OCA-B. Chromatin immunoprecipitation experiments revealed that XBP-1(S) binds to the OBF-1/BOB-1/OCA-B promoter in the plasmacytoma line and in primary B cells not only during plasma cell differentiation, but also in response to classical UPR activation. Gel shift assays suggest that XBP-1(S) binding occurs through a UPR element conserved in both murine and human OBF-1/BOB-1/OCA-B promoters as opposed to endoplasmic reticulum stress response elements. Our studies are the first to identify direct downstream targets of XBP-1(S) during either plasma cell differentiation or the UPR. In addition, our data further define the XBP-1(S)-binding sequence and provide yet another role for this protein as a master regulator of plasma cell differentiation.
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1 This work was supported by National Institutes of Health Grant GM54068 (to L.M.H.), the Cancer Center CORE Grant CA21765, and the American Lebanese Syrian Associated Charities of St. Jude Children’s Research Hospital.
2 Address correspondence and reprint requests to Linda M. Hendershot, St. Jude Children’s Research Hospital, 332 North Lauderdale Street, Danny Thomas Research Tower 5063, Memphis, TN 38105. E-mail address: linda.hendershot{at}stjude.org
3 Abbreviations used in this paper: ER, endoplasmic reticulum; ATF, activating transcription factor; ChIP, chromatin immunoprecipitation; ERSE, ER stress response element; m, membrane form of the H chain; s, secretory form of the H chain; IRF4, IFN regulatory factor 4; PERK, PKR-like endoplasmic reticulum kinase; shRNA, small hairpin RNA; shXBP-1, small hairpin XBP-1; UPR, unfolded protein response; UPRE, UPR element; WT, wild type; XBP-1(S), spliced form of XBP-1; Hsc70, heat shock cognate protein 70.
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  M. Dong, J. P. Bridges, K. Apsley, Y. Xu, and T. E. Weaver ERdj4 and ERdj5 Are Required for Endoplasmic Reticulum-associated Protein Degradation of Misfolded Surfactant Protein C Mol. Biol. Cell, June 1, 2008; 19(6): 2620 - 2630. [Abstract] [Full Text] [PDF]
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