title: E3 ubiquitin ligase CHIP facilitates Toll-like receptor signaling by recruiting and polyubiquitinating Src and atypical PKC{zeta}.
abstract: The carboxyl terminus of constitutive heat shock cognate 70 (HSC70)-interacting protein (CHIP, also known as Stub1) is a U box-containing E3 ubiquitin ligase that is important for protein quality control. The role of CHIP in innate immunity is not known. Here, we report that CHIP knockdown inhibits Toll-like receptor (TLR) 4- and TLR9-driven signaling, but not TLR3-driven signaling; proinflammatory cytokine and type 1 interferon (IFN) production; and maturation of antigen-presenting cells, including macrophages and dendritic cells. We demonstrate that CHIP can recruit the tyrosine kinase Src and atypical protein kinase C ζ (PKCζ) to the TLR complex, thereby leading to activation of IL-1 receptor-associated kinase 1, TANK-binding kinase 1, and IFN regulatory factors 3 and 7. CHIP acts as an E3 ligase for Src and PKCζ during TLR signaling. CHIP-mediated enhancement of TLR signaling is inhibited by IFNAR deficiency or expression of ubiquitination resistant mutant forms of Src or PKCζ. These findings suggest that CHIP facilitates the formation of a TLR signaling complex by recruiting, ubiquitinating, and activating Src and PKCζ.
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058, China; National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai200433, China.
authors.forename: Mingjin
authors.initials: M
authors.lastname: Yang
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.forename: Xuhui
authors.initials: X
authors.lastname: Zhu
authors.forename: Songqing
authors.initials: S
authors.lastname: Tang
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
authors.forename: Taoyong
authors.initials: T
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D055785:Gene Knockdown Techniques; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D050883:HSC70 Heat-Shock Proteins; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D016328:NF-kappa B; D011493:Protein Kinase C; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9; D044767:Ubiquitin-Protein Ligases; D019061:src-Family Kinases; D000099221:Protein Kinase C zeta; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse