Editors' ChoiceInnate Immunity


Sci. Signal.  26 Jul 2011:
Vol. 4, Issue 183, pp. ec203
DOI: 10.1126/scisignal.4183ec203

Recognition of viral particles by Toll-like receptors (TLRs) 7 and 9 induces the recruitment of IRAK1 [interleukin 1 (IL-1) receptor–associated kinase 1] to the TLR complex, where it is phosphorylated by IRAK4. Activated IRAK1 then dissociates from the TLR complex and activates the transcription factor IRF7, which translocates to the nucleus and mediates transcription of the gene encoding interferon-α (IFN-α). Tun-Kyi et al. explored the role of Pin1, an enzyme that induces cis-trans isomerization of proline residues after a phosphorylated serine or threonine residue, in the activation of IRAK1. Pin1-deficient plasmacytoid dendritic cells (pDCs) produced less IFN in response to stimulation of TLR7 or TLR9 with purified ligand or virus than did wild-type pDCs. IRAK1 was identified as a Pin1 substrate, and the interaction required the WW domain of Pin1 and phosphorylation of IRAK1 at Ser131, Ser144, or Ser173. In Pin1-deficient mouse embryo fibroblasts (MEFs) or pDCs, activation of IRAK1 in response to TLR7 or TLR9 ligation was attenuated. This was due in part to stable association of IRAK1 with the TLR complex, suggesting that Pin1 activity released IRAK1 from the TLR complex. Nuclear translocation of IRF7 in response to TLR7 or TLR9 ligands was impaired in Pin1-deficient pDCs. Furthermore, the activity of an IRF7 reporter gene was reduced in Pin1-deficient MEFs, an effect that was rescued by reconstitution with wild-type Pin1 but not with a catalytically inactive mutant or a mutant that could not bind to IRAK1. MEFs expressing IRAK1 S131A, S144A, or S173A (mutations that abolished phosphorylation of the residues preceding the proline residues targeted by Pin1) in various combinations showed reduced IRF7 transcriptional activity and diminished production of IFN-α, as indicated by the lower antiviral activity of supernatants from these MEFs against vesicular stomatitis virus. Pin1-deficient mice produced less IFN-α than did wild-type mice in response to injection with TLR7 or TLR9 ligands, were more susceptible to infection with mouse cytomegalovirus (a virus that activates TLR9), and showed less expansion of CD8+ T cells in response to antigen. Thus, Pin1 promotes the activation of IRAK1 and the production of IFN in antiviral responses.

A. Tun-Kyi, G. Finn, A. Greenwood, M. Nowak, T. H. Lee, J. M. Asara, G. C. Tsokos, K. Fitzgerald, E. Israel, X. Li, M. Exley, L. K. Nicholson, K. P. Lu, Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon–mediated immunity. Nat. Immunol. 12, 733–741 (2011). [PubMed]