UBP43 is a novel regulator of interferon signaling independent of its ISG15 isopeptidase activity

Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.
The EMBO Journal (Impact Factor: 10.43). 07/2006; 25(11):2358-67. DOI: 10.1038/sj.emboj.7601149
Source: PubMed


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.

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    • "To further delineate the cause of the decreased chemokine production the expression of 2 essential ISGs in the IFNstimulated PBMC, USP18, and IRF7 was investigated. Ubiquitin-specific peptidase 18 (encoded by USP18) is a classical ISG that provides a strong negative feedback signal serving to downregulate the activation of the IFN-activated Janus kinase-signal transducer and activator of transcription ( Jak-STAT) pathways (Malakhova and others 2006). Importantly , the mRNA expression of USP18 was significantly lower in AAD patients than healthy controls after IFN stimulation, indicating that the poor response to IFNs is not selective for chemokine production. "
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    • "Similarly, ubiquitin carboxy-terminal hydrolase 18 (USP18)/Ubiquitin protease 43 (UBP43) was shown to be required for induction of a long-lasting desensitized state [49]. Binding of UBP43 to IFNAR2 in vivo displaced JAK1 from IFNAR2 and led to the inhibition of the downstream phosphorylation cascade and other signaling events [51]. Of note, administration of PEG-IFN alpha 2b in patients with CHC was shown to activate the JAK/STAT pathway only during the first day following injection, and then rapidly induced SOCS1, SOCS3 and UBP43 expression, despite the fact that the serum concentrations of PEG-IFN alpha 2 remained high for the entire week. "
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    • "Suppressor of cytokine signalling (SOCS) proteins are rapidly induced by activated STATs and provide an early negative feedback loop [27–29]. Ubiquitin-specific peptidase 18 (USP18, also designated UBP43) is another important negative regulator in type I IFN signalling [30]. USP18 is a key mediator of the refractoriness of liver cells to continuous stimulation with IFN-a [31]. "
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