title: Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity.
abstract: Toll-like receptors (TLRs) shape innate and adaptive immunity to microorganisms. The enzyme IRAK1 transduces signals from TLRs, but mechanisms for its activation and regulation remain unknown. We found here that TLR7 and TLR9 activated the isomerase Pin1, which then bound to IRAK1; this resulted in activation of IRAK1 and facilitated its release from the receptor complex to activate the transcription factor IRF7 and induce type I interferons. Consequently, Pin1-deficient cells and mice failed to mount TLR-mediated, interferon-dependent innate and adaptive immune responses. Given the critical role of aberrant activation of IRAK1 and type I interferons in various immune diseases, controlling IRAK1 activation via inhibition of Pin1 may represent a useful therapeutic approach.
authors: Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors: Adrian
authors: A
authors: Tun-Kyi
authors: Greg
authors: G
authors: Finn
authors: Alex
authors: A
authors: Greenwood
authors: Michael
authors: M
authors: Nowak
authors: Tae Ho
authors: TH
authors: Lee
authors: John M
authors: JM
authors: Asara
authors: George C
authors: GC
authors: Tsokos
authors: Kate
authors: K
authors: Fitzgerald
authors: Elliot
authors: E
authors: Israel
authors: Xiaoxia
authors: X
authors: Li
authors: Mark
authors: M
authors: Exley
authors: Linda K
authors: LK
authors: Nicholson
authors: Kun Ping
authors: KP
authors: Lu
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D015151:Immunoblotting; D050856:Interferon Regulatory Factor-1 / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000276:immunology; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D019696:Peptidylprolyl Isomerase / Q000276:immunology*; D010766:Phosphorylation / Q000276:immunology; D012313:RNA / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000276:immunology*
chemical_list: D050856:Interferon Regulatory Factor-1; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D051193:Toll-Like Receptors; D012313:RNA; D016899:Interferon-beta; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse