Identification of gp96 as a novel target for treatment of autoimmune disease in mice.
Heat shock proteins have been implicated as endogenous activators for dendritic cells (DCs). Chronic expression of heat shock protein gp96 on cell surfaces induces significant DC activations and systemic lupus erythematosus (SLE)-like phenotypes in mice. However, its potential as a therapeutic target against SLE remains to be evaluated. In this work, we conducted chemical approach to determine whether SLE-like phenotypes can be compromised by controlling surface translocation of gp96. From screening of chemical library, we identified a compound that binds and suppresses surface presentation of gp96 by facilitating its oligomerization and retrograde transport to endoplasmic reticulum. In vivo administration of this compound reduced maturation of DCs, populations of antigen presenting cells, and activated B and T cells. The chemical treatment also alleviated the SLE-associated symptoms such as glomerulonephritis, proteinuria, and accumulation of anti-nuclear and -DNA antibodies in the SLE model mice resulting from chronic surface exposure of gp96. These results suggest that surface translocation of gp96 can be chemically controlled and gp96 as a potential therapeutic target to treat autoimmune disease like SLE.
Han
Jung Min
JM
Center for Medicinal Protein Network and Systems Biology, College of Pharmacy, Seoul National University, Seoul, Republic of Korea.
Kwon
Nam Hoon
NH
Lee
Jin Young
JY
Jeong
Seung Jae
SJ
Jung
Hee Jung
HJ
Kim
Hyeong Rae
HR
Li
Zihai
Z
Kim
Sunghoon
S
D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology; D001327:Autoimmune Diseases / Q000235:genetics*; D001402:B-Lymphocytes / Q000166:cytology; D002462:Cell Membrane / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D013154:Spleen / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology
D008562:Membrane Glycoproteins; C053387:endoplasmin