Article
- The EMBO Journal (2006) 25, 2358 - 2367
- doi:10.1038/sj.emboj.7601149
Published online: 18 May 2006
Subject Categories:
UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity
Oxana A Malakhova1, Keun II Kim1,a, Jiann-Kae Luo1, Weiguo Zou1, KG Suresh Kumar2, Serge Y Fuchs2, Ke Shuai3 and Dong-Er Zhang1
- Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA
- Department of Animal Biology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USA
- Division of Hematology/Oncology, School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
Correspondence to:
Dong-Er Zhang, Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-L51, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. Tel.: +1 858 784 9558; Fax: +1 858 784 9593; E-mail: dzhang@scripps.edu
aPresent address: Department of Biological Science, Sookmyung Women's University, Seoul 140-742, Korea
Received 12 December 2005; Accepted 21 April 2006
Abstract
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.
Keywords:
- interferon (IFN),
- ISG15,
- JAK,
- STAT,
- UBP43 (USP18)
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