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STAT3 regulation by S‐nitrosylation: implication for inflammatory disease (555.8)
Author(s) -
Won Jeseong,
Kim Jinsu,
Singh Avtar,
Sharma Anand,
Singh Inderjit
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.555.8
Subject(s) - s nitrosoglutathione , nitrosylation , phosphorylation , stat3 , microbiology and biotechnology , s nitrosylation , nitric oxide , chemistry , microglia , biology , signal transduction , biochemistry , inflammation , immunology , glutathione , cysteine , organic chemistry , enzyme
S‐nitrosylation and S‐glutathionylation, redox based modifications of protein thiols, are recently emerging as an important signaling mechanisms. Here, we assessed S‐nitrosylation based regulation of JAK2/STAT3 pathway that plays critical roles in immune/inflammatory responses and tumorigenesis. Our studies show that STAT3 in stimulated microglia underwent two distinct redox‐dependent modifications, S‐nitrosylation and S‐glutathionylation. STAT3 S‐nitrosylation was associated with iNOS‐produced nitric oxide (NO) and S‐nitrosoglutathione (GSNO), while S‐glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr705). Consequently, the IL‐6 induced microglial proliferation and associated gene expressions were also reduced. In cell free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO‐mediated mechanisms inhibit STAT3 phosphorylation through S‐nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys259 was the target Cys residue of GSNO‐mediated S‐nitrosylation of STAT3. The replacement of Cys259 residue with Ala abolished the inhibitory role of GSNO in IL‐6‐induced STAT3 phosphorylation and transactivation, suggesting the role of Cys259 S‐nitrosylation in STAT3 phosphorylation. Our results indicate the regulation of STAT3 by NO‐based post‐translational modification (S‐nitrosylation). These findings have important implications for development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer. Grant Funding Source : NS072511, BX001062, NS037766 and BX001072