UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity
UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity
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DOI：
10.1038/sj.emboj.7601149
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发表时间：
2006-06-07
期刊：
影响因子：
11.4
通讯作者：
Zhang, Dong-Er
中科院分区：
文献类型：
--
作者：
Malakhova, Oxana A.;Kim, Keun Il;Zhang, Dong-Er
干扰素（IFN）通过激活Janus激酶-信号转导子和转录激活子（JAK-STAT）途径调节多种细胞功能。缺乏Ubp 43，一种IFN诱导的ISG 15去结合酶，导致在Ubp 43-/-小鼠中的IFN超敏反应，表明Ubp 43在下调IFN应答中的重要功能。在这里，我们表明，Ubp 43负调控IFN信号独立的异肽酶对ISG 15的活性。Ubp 43通过在IFN受体水平下调JAK-STAT途径而特异性地对I型IFN信号传导起作用。利用分子、生物化学和遗传学方法，我们证明Ubp 43特异性结合IFNAR 2受体亚基，并通过阻断JAK和IFN受体之间的相互作用来抑制受体相关JAK 1的活性。这些数据暗示Ubp 43作为一种新的体内抑制剂的信号转导途径，特别是触发I型IFN。
Interferons (IFNs) regulate diverse cellular functions through activation of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Lack of Ubp43, an IFN-inducible ISG15 deconjugating enzyme, leads to IFN hypersensitivity in ubp43-/- mice, suggesting an important function of Ubp43 in downregulation of IFN responses. Here, we show that Ubp43 negatively regulates IFN signaling independent of its isopeptidase activity towards ISG15. Ubp43 functions specifically for type I IFN signaling by downregulating the JAK-STAT pathway at the level of the IFN receptor. Using molecular, biochemical, and genetic approaches, we demonstrate that Ubp43 specifically binds to the IFNAR2 receptor subunit and inhibits the activity of receptor-associated JAK1 by blocking the interaction between JAK and the IFN receptor. These data implicate Ubp43 as a novel in vivo inhibitor of signal transduction pathways that are specifically triggered by type I IFN.