2. Academic Validation
  3. MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239

MFHAS1 suppresses TLR4 signaling pathway via induction of PP2A C subunit cytoplasm translocation and inhibition of c-Jun dephosphorylation at Thr239

  • Mol Immunol. 2017 Aug;88:79-88. doi: 10.1016/j.molimm.2017.06.017.
Qiqing Shi 1,  Bo Xiong 2,  Jing Zhong 2,  Huihui Wang 2,  Duan Ma 3,  Changhong Miao 4
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Anesthesiology, Children's Hospital of Fudan University, Shanghai, 201102, China.
  • 2 Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
  • 3 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; Children's Hospital of Fudan University, Shanghai, 201102, China. Electronic address: duanma@fudan.edu.cn.
  • 4 Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. Electronic address: miao_changhong@163.com.
PMID: 28609714 DOI: 10.1016/j.molimm.2017.06.017
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.

Keywords

AP-1; LPS; MFHAS1; PP2A; TLR4 signaling pathway; c-Jun.

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