Malakhova Oxana A, Kim Keun Il, Luo Jiann-Kae, Zou Weiguo, Kumar K G Suresh, Fuchs Serge Y, Shuai Ke, Zhang Dong-Er
Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
EMBO J. 2006 Jun 7;25(11):2358-67. doi: 10.1038/sj.emboj.7601149. Epub 2006 May 18.
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.
干扰素（IFNs）通过激活Janus激酶-信号转导子和转录激活子（JAK-STAT）途径来调节多种细胞功能。缺乏Ubp43（一种IFN诱导的ISG15去共轭酶）会导致ubp43基因敲除小鼠对IFN过敏，这表明Ubp43在下调IFN反应中具有重要功能。在此，我们表明Ubp43独立于其对ISG15的异肽酶活性，对IFN信号传导起负调节作用。Ubp43通过在IFN受体水平下调JAK-STAT途径，特异性地作用于I型IFN信号传导。使用分子、生化和遗传学方法，我们证明Ubp43特异性结合IFNAR2受体亚基，并通过阻断JAK与IFN受体之间的相互作用来抑制受体相关JAK1的活性。这些数据表明Ubp43是I型IFN特异性触发的信号转导途径的新型体内抑制剂。
