Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032412-25
Application #
7899871
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Peyman, John A
Project Start
1986-07-15
Project End
2012-07-31
Budget Start
2010-08-01
Budget End
2012-07-31
Support Year
25
Fiscal Year
2010
Total Cost
$469,980
Indirect Cost

  Institution

Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Public Health
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02115

  Publications

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
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
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
Vidal, Rene L; Figueroa, Alicia; Court, Felipe A et al. (2012) Targeting the UPR transcription factor XBP1 protects against Huntington's disease through the regulation of FoxO1 and autophagy. Hum Mol Genet 21:2245-62
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
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

Showing the most recent 10 out of 49 publications