In the current funding period, we have discovered that the transcription factor XBP-1, isolated in our laboratory, is required for plasma cell differentiation and antibody production. XBP-1 is the only substrate of IRE1a (IRE1), the ER transmembrane endoribonuclease and kinase that mediates the Unfolded Protein Response (UPR). Our studies have established a link between plasma cell differentiation and the UPR. We have provided evidence that XBP-1 functions to expand the secretory machinery in B cells and acinar cells and is important in dendritic cell survival. Further, XBP-1 is a major target of proteasome inhibitors in the treatment of multiple myeloma. The availability of an XBP-1 flox/flox mouse strain as well as IRE-/- lymphoid chimeras generated in the current funding period will allow us to explore many unanswered questions about the function of IRE1, XBP-1 and the UPR in pre B (IRE1) and plasma cell (XBP-1) differentiation, in normal and malignant dendritic cell survival and function, in autoimmune disease and in multiple myeloma. In the next funding period we propose to 1) Further explore the role of XBP-1 in B cell commitment.2) Identify novel components of the IRE1 signaling pathway. 3) Investigate the function of XBP-1 and the UPR in normal and malignant dendritic cells (DCs). 4) Examine the role of XBP-1 in autoimmune disease.5) Investigate the requirement of XBP-1 for the development and propagation of plasma cell neoplasms.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Cellular and Molecular Immunology - A Study Section (CMIA)
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Peyman, John A
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Harvard University
Schools of Public Health
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Chen, Xi; Iliopoulos, Dimitrios; Zhang, Qing et al. (2014) XBP1 promotes triple-negative breast cancer by controlling the HIF1? pathway. Nature 508:103-107
Cho, Jin A; Lee, Ann-Hwee; Platzer, Barbara et al. (2013) The unfolded protein response element IRE1? senses bacterial proteins invading the ER to activate RIG-I and innate immune signaling. Cell Host Microbe 13:558-569
Hur, Kyu Yeon; So, Jae-Seon; Ruda, Vera et al. (2012) IRE1? activation protects mice against acetaminophen-induced hepatotoxicity. J Exp Med 209:307-18
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Hu, Yang; Park, Kevin K; Yang, Liu et al. (2012) Differential effects of unfolded protein response pathways on axon injury-induced death of retinal ganglion cells. Neuron 73:445-52
So, Jae-Seon; Hur, Kyu Yeon; Tarrio, Margarite et al. (2012) Silencing of lipid metabolism genes through IRE1?-mediated mRNA decay lowers plasma lipids in mice. Cell Metab 16:487-99
Hetz, Claudio; Martinon, Fabio; Rodriguez, Diego et al. (2011) The unfolded protein response: integrating stress signals through the stress sensor IRE1?. Physiol Rev 91:1219-43
Martinon, Fabio; Glimcher, Laurie H (2011) Regulation of innate immunity by signaling pathways emerging from the endoplasmic reticulum. Curr Opin Immunol 23:35-40
Hess, David A; Humphrey, Sean E; Ishibashi, Jeff et al. (2011) Extensive pancreas regeneration following acinar-specific disruption of Xbp1 in mice. Gastroenterology 141:1463-72
Hetz, Claudio; Glimcher, Laurie H (2011) Protein homeostasis networks in physiology and disease. Curr Opin Cell Biol 23:123-5

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