MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239 |
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| Affiliation: | 1. Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China;2. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Collaborative Innovation Center of Genetics and Development, Department of Biochemistry and Molecular Biology, Institute of Biomedical Sciences, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China;3. Department of Anesthesiology, Children’s Hospital of Fudan University, Shanghai, 201102, China;4. Children’s Hospital of Fudan University, Shanghai, 201102, China;1. Department of Pathogenic Biology and Immunology, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education of China, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, No.76 Yanta West Road, Xi’an, Shaanxi,710061, China;2. Department of Pathology, the 2nd Affiliated hospital of Medical College, Xi’an Jiaotong University, Xi’an, Shaanxi, 710004, China;3. Departments of Pharmacology and Toxicology and Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755;5. Departments of Pathology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755,;4. Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03766,;6. Veterans Affairs Medical Center, White River Junction, Vermont 05001,;12. Department of Pharmacology, The University of Iowa, Iowa City, Iowa 52242;3. Dipartimento di Scienze Mediche e Biologiche Università degli Studi di Udine, P.le Kolbe 4–33100 Udine, Italy and;4. CNRS UMR 5237 CRBM Montpellier University 1919 Route de Mende, 34293 Montpellier Cedex 5, France;1. Institute for Cardiovascular Science & Department of Cardiovascular Surgery of the First Affiliated Hospital, Soochow University, Suzhou 215006, China;2. Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215006, China;3. Jiangsu Province Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agriculture University, Nanjing 210000, China;4. Orthopedic Department of the Second Affiliated Hospital of Soochow University, Suzhou 215000, China;5. Emergency Department of the First Affiliated Hospital of Soochow University, Suzhou 215006, China;6. Department of Cardiology of the First Affiliated Hospital, Soochow University, Suzhou 215006, China;1. Division of Pharmacology, CSIR-Central Drug Research Institute, Lucknow, 226031, India;2. Academy of Scientific and Innovative Research, CSIR-CDRI, India |
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| Abstract: | TLR4, an important Toll-like receptor in innate immunity, can be activated by LPS and induce proinflammatory cytokines to resist invasion of pathogenic microorganism, but excessive inflammation can trigger tissue injury. Many genes negatively regulate TLR4 signaling pathway. Recent studies found that malignant fibrous histiocytoma amplified sequence 1 (MFHAS1) suppressed the expression of cytokine IL6 in Raw264.7 cells stimulated by LPS, but the mechanisms remained unclear. This study investigated the role of MFHAS1 in TLR4 signaling pathway and the possible mechanisms implicated. The results indicated that the expression of MFHAS1 was significantly increased in cells stimulated with LPS. Up-regulation of MFHAS1 effectively suppressed inflammatory cytokine expression in cells exposed to LPS, whereas down-regulation of MFHAS1 markedly increased inflammatory cytokines expression. Co-immunoprecipitation, pull-down and immunofluorescence tests demonstrated that MFHAS1 combined with the B and C subunits of PP2A and induced cytoplasm translocation of the C subunit, leading to decrease dephosphorylation of c-Jun at Thr239 and increase degradation of c-Jun. Reduction of c-Jun protein results in decreased AP-1 activity, which is independent of inhibition of JNK or p38MAPK phosphorylation. Taken together, these results indicate that MFHAS1 suppresses TLR4 signaling pathway through induction of PP2A C subunit cytoplasm translocation and subsequent c-Jun degradation, leading finally to decrease AP-1 activity and cytokines expression. |
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| Keywords: | MFHAS1 LPS TLR4 signaling pathway PP2A AP-1 c-Jun |
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