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.

17 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune Addison's disease (AAD) is a disorder caused by an immunological attack on the adrenal cortex. The interferon (IFN)-inducible chemokine CXCL10 is elevated in serum of AAD patients, suggesting a peripheral IFN signature. However, CXCL10 can also be induced in adrenocortical cells stimulated with IFNs, cytokines, or microbial components. We therefore investigated whether peripheral blood mononuclear cells (PBMCs) from AAD patients display an enhanced propensity to produce CXCL10 and the related chemokine CXCL9, after stimulation with type I or II IFNs or the IFN inducer poly (I:C). Although serum levels of CXCL10 and CXCL9 were significantly elevated in patients compared with controls, IFN stimulated patient PBMC produced significantly less CXCL10/CXCL9 than control PBMC. Low CXCL10 production was not significantly associated with medication, disease duration, or comorbidities, but the low production of poly (I:C)-induced CXCL10 among patients was associated with an AAD risk allele in the phosphatase nonreceptor type 22 (PTPN22) gene. PBMC levels of total STAT1 and -2, and IFN-induced phosphorylated STAT1 and -2, were not significantly different between patients and controls. We conclude that PBMC from patients with AAD are deficient in their response to IFNs, and that the adrenal cortex itself may be responsible for the increased serum levels of CXCL10.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 05/2015; DOI:10.1089/jir.2014.0171 · 2.00 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The clinical exploitation of type I interferon (IFN) as an antiviral and antineoplastic agent is based on the original properties attributed to this cytokine family, with schedules and modalities that reflect their antiviral and antiproliferative activities. Nevertheless, type I IFN has emerged as a central activator of the innate immunity, with the capacity to induce potent immune responses against foreign pathological agents. Physiologically, type I IFN is produced in large amounts by plasmacytoid dendritic cells and is rapidly silenced by self-regulatory mechanisms. The current schedule of treatment for infectious diseases, especially chronic hepatitis C, as well as for a limited number of hematological and solid tumors is based on the continuous administration of either intermediate or high dose recombinant or pegylated type I IFN, regardless of emerging data on the viral resistance, host genetic variants predicting treatment outcome and multiple mechanisms of refractoriness. New administration schedules, the combination of type I IFN with new drugs and increased monitoring of patients’ susceptibility are expected to provide a new life to this valuable cytokine.
    Cytokine & Growth Factor Reviews 12/2014; 26(2). DOI:10.1016/j.cytogfr.2014.12.006 · 5.36 Impact Factor
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Hepatitis C virus has been identified a quarter of a decade ago as a leading cause of chronic viral hepatitis that can lead to cirrhosis and hepatocellular carcinoma. Only a minority of patients can clear the virus spontaneously during acute infection. Elimination of HCV during acute infection correlates with a rapid induction of innate, especially interferon (IFN) induced genes, and a delayed induction of adaptive immune responses. However, the majority of patients is unable to clear the virus and develops viral persistence in face of an ongoing innate and adaptive immune response. The virus has developed several strategies to escape these immune responses. For example, to escape innate immunity, the HCV NS3/4A protease can efficiently cleave and inactivate two important signalling molecules in the sensory pathways that react to HCV pathogen-associated molecular patterns (PAMPs) to induce IFNs, i.e., the mitochondrial anti-viral signalling protein (MAVS) and the Toll-IL-1 receptor-domain-containing adaptor-inducing IFN-β (TRIF). Despite these escape mechanisms, IFN-stimulated genes (ISGs) are induced in a large proportion of patients with chronic infection. Of note, chronically HCV infected patients with constitutive IFN-stimulated gene (ISG) expression have a poor response to treatment with pegylated IFN-α (PegIFN-α) and ribavirin. The mechanisms that protect HCV from IFN-mediated innate immune reactions are not entirely understood, but might involve blockade of ISG protein translation at the ribosome, localization of viral replication to cell compartments that are not accessible to anti-viral IFN-stimulated effector systems, or direct antagonism of effector systems by viral proteins. Escape from adaptive immune responses can be achieved by emergence of viral escape mutations that avoid recognition by antibodies and T cells. In addition, chronic infection is characterized by the presence of functionally and phenotypically altered NK and T cell responses that are unable to clear the virus but most likely contribute to the ongoing liver disease. In this review, we will summarize current knowledge about the role of innate and adaptive immune responses in determining the outcome of HCV infection.
    Journal of Hepatology 11/2014; 61(1). DOI:10.1016/j.jhep.2014.06.035 · 11.34 Impact Factor
Show more


17 Reads
Available from