Heat shock protein gp96 is a key downstream chaperone in the endoplasmic reticulum (ER) that mediates ER unfolded protein responses (UPR). Cell surface expression of gp96 in a transgenic mouse leads to spontaneous lupus-like autoimmune disease which is dependent on commensal bacteria and Toll-like receptor 4 (TLR4). This finding, together with the discovery that gp96 is a master chaperone for TLRs, has moved the field forward significantly: we now hypothesize that gp96 tunes the immune system by chaperoning TLRs but not by signaling through TLRs;depending on its expression level and location, gp96 can break tolerance if upregulated and can confer immunodeficiency if compromised in expression or function. The previously unappreciated roles of TLR4 in lupus have been validated by lupus in TLR4-overexpressing mice. Studies of the mechanism of autoimmunity in gp96 transgenic mice have also uncovered the potential impact of chronic TLR hyperresponsiveness to commensal flora on IL-10-producing CD4? T cells (TR1) and IL-17-secreting CD4 cells (TH17) in vivo. In this proposal, we will critically address the hypothesis that TLR4 amplification at either DNA level or post translational level significantly impact the biology (priming, maintenance and function) of both TR1 and TH17, leading to breakdown of peripheral tolerance. We will also define the hierarchy of TLRs in driving lupus with particular focus on the roles of nucleic acid-sensing TLRs in our model. Our study is of fundamental significance in understanding the roles of TLRs in immunity and tolerance via regulating TR1 and TH17, since the dysregulation of these cell types has been increasingly implicated in autoimmune diseases. Our recent findings that the surface expression of gp96 is highly regulated in vivo and that the increased expression of gp96 on the cell surface correlates with human lupus highlight the clinical relevance of our study.

Public Health Relevance

This project addresses the mechanism of lupus, which has implications in the understanding of general immunobiology, cancer immunity and other autoimmune diseases.
We aim to prove the hypothesis that the overexpression of particular cell surface stress proteins leads to heightened responses against microbes, which in turn triggers the development of autoimmunity through complex actions on two critical immune regulatory cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI077283-09
Application #
8230772
Study Section
Transplantation, Tolerance, and Tumor Immunology (TTT)
Program Officer
Johnson, David R
Project Start
2009-03-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$361,412
Indirect Cost
$116,387
Name
Medical University of South Carolina
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Thaxton, Jessica E; Liu, Bei; Zheng, Pan et al. (2014) Deletion of CD24 impairs development of heat shock protein gp96-driven autoimmune disease through expansion of myeloid-derived suppressor cells. J Immunol 192:5679-86
Morales, Crystal; Rachidi, Saleh; Hong, Feng et al. (2014) Immune chaperone gp96 drives the contributions of macrophages to inflammatory colon tumorigenesis. Cancer Res 74:446-59
Zhang, Yongliang; Helke, Kristi L; Coelho, Sergio G et al. (2014) Essential role of the molecular chaperone gp96 in regulating melanogenesis. Pigment Cell Melanoma Res 27:82-9
Jiang, Wei; Zhang, Lumin; Lang, Ren et al. (2014) Sex differences in monocyte activation in systemic lupus erythematosus (SLE). PLoS One 9:e114589
Hua, Yunpeng; White-Gilbertson, Shai; Kellner, Joshua et al. (2013) Molecular chaperone gp96 is a novel therapeutic target of multiple myeloma. Clin Cancer Res 19:6242-51
Hong, Feng; Liu, Bei; Chiosis, Gabriela et al. (2013) *7 helix region of *I domain is crucial for integrin binding to endoplasmic reticulum chaperone gp96: a potential therapeutic target for cancer metastasis. J Biol Chem 288:18243-8
Wu, Shuang; Hong, Feng; Gewirth, Daniel et al. (2012) The molecular chaperone gp96/GRP94 interacts with Toll-like receptors and integrins via its C-terminal hydrophobic domain. J Biol Chem 287:6735-42
Wu, Shuang; Dole, Krystal; Hong, Feng et al. (2012) Chaperone gp96-independent inhibition of endotoxin response by chaperone-based peptide inhibitors. J Biol Chem 287:19896-903
Staron, Matthew; Wu, Shuang; Hong, Feng et al. (2011) Heat-shock protein gp96/grp94 is an essential chaperone for the platelet glycoprotein Ib-IX-V complex. Blood 117:7136-44
Liu, Bei; Yang, Yi; Qiu, Zhijuan et al. (2010) Folding of Toll-like receptors by the HSP90 paralogue gp96 requires a substrate-specific cochaperone. Nat Commun 1:79

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