391회 Negative regulation of interferon-a/b signaling by deISGylating p…

391회

연사 :  Kim Keunil,  

제목:   Negative regulation of interferon-a/b signaling by deISGylating protease UBP43

Abstract

  Interferons (IFNs) regulate diverse cellular functions through the activation of Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway and are critical for innate immune responses. Negative regulation of IFN signaling by various proteins in response to cytokine stimulation plays an important role in restricting the extent and duration of the signaling. Lack of UBP43, an ISG15 deconjugating enzyme, leads to IFN hypersensitivity in cells and mice suggesting an important function of UBP43 in down-regulation of IFN signaling. In UBP43-deficient cells, IFN-a/b induces a prolonged Stat1 tyrosine phosphorylation, DNA binding of ISGF3 complex and IFN-mediated gene activation and also accumulation of ISG15 conjugated proteins. UBP43-deficient mice are hypersensitive to IFN-inducing reagents, such as polyI-C and lipopolysaccharide than wild-type, however, much more resistant against viral and bacterial infection. Interestingly, we found that UBP43 negatively regulates IFN signaling independent of its isopeptidase activity towards ISG15. UBP43 functions IFN-a/b signaling by down regulating JAK-STAT pathway at the level of the IFN receptor, but is not involved in the control of receptor proteolysis or sustaining the level of the IFN receptor at the cell surface. Instead, UBP43 specifically binds to the IFNAR2 receptor subunit and inhibits the activity of the receptor-associated JAK1 by blocking the interaction between JAK and the IFN receptor. These data implicate UBP43 as a novel type of inhibitors of signal transduction pathways that are specifically triggered by IFN-a/b.