title: Protein tyrosine phosphatase with proline-glutamine-serine-threonine-rich motifs negatively regulates TLR-triggered innate responses by selectively inhibiting IκB kinase β/NF-κB activation.
abstract: TLRs are essential for sensing the invading pathogens and initiating protective immune responses. However, aberrant activation of TLR-triggered inflammatory innate responses leads to the inflammatory disorders and autoimmune diseases. The molecular mechanisms that fine-tune TLR responses remain to be fully elucidated. Protein tyrosine phosphatase with proline-glutamine-serine-threonine-rich motifs (PTP-PEST) has been shown to be important in cell adhesion, migration, and also T cell and B cell activation. However, the roles of PTP-PEST in TLR-triggered immune response remain unclear. In this study, we report that PTP-PEST expression was upregulated in macrophages by TLR ligands. PTP-PEST inhibited TNF-α, IL-6, and IFN-β production in macrophages triggered by TLR3, TLR4, and TLR9. Overexpression of catalytically inactive mutants of PTP-PEST abolished the inhibitory effects, indicating that PTP-PEST inhibits TLR response in a phosphatase-dependent manner. Accordingly, PTP-PEST knockdown increased TLR3, -4, and -9-triggered proinflammatory cytokine and type I IFN production. PTP-PEST selectively inhibited TLR-induced NF-κB activation, whereas it had no substantial effect on MAPK and IFN regulatory factor 3 activation. Moreover, PTP-PEST directly interacted with IκB kinase β (IKKβ) then inhibited IKKβ phosphorylation at Ser(177/181) and Tyr(188/199), and subsequently suppressed IKKβ activation and kinase activity as well as downstream NF-κB activation, resulting in suppression of the TLR-triggered innate immune response. Thus, PTP-PEST functions as a feedback-negative regulator of TLR-triggered innate immune responses by selectively impairing IKKβ/NF-κB activation.
authors.affiliation: National Key Laboratory of Medical Immunology, Second Military Medical University, Shanghai 200433, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
authors.forename: Yingke
authors.initials: Y
authors.lastname: Li
authors.forename: Xuhui
authors.initials: X
authors.lastname: Zhu
authors.forename: Zhenzhen
authors.initials: Z
authors.lastname: Zhan
authors.forename: Jun
authors.initials: J
authors.lastname: Meng
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics / Q000276:immunology; D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology*; D005973:Glutamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate / Q000235:genetics; D017737:Macrophages, Peritoneal / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D025941:Protein Interaction Mapping / Q000379:methods; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000096:biosynthesis / Q000737:chemistry* / Q000502:physiology*; D012694:Serine / Q000378:metabolism; D013912:Threonine / Q000378:metabolism; D014018:Tissue Distribution / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D051193:Toll-Like Receptors; D005973:Glutamine; D013912:Threonine; D012694:Serine; D011392:Proline; D051550:I-kappa B Kinase; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12