Ligand-independent pathway that controls stability of interferon alpha receptor

Department of Animal Biology and Mari Lowe Center for Comparative Oncology Research, School of Veterinary Medicine, University of Pennsylvania, Room 316 Hill Pavilion, 380 S University Avenue, Philadelphia, PA 19104-4539, USA.
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 04/2008; 367(2):388-93. DOI: 10.1016/j.bbrc.2007.12.137
Source: PubMed


Ligand-specific negative regulation of cytokine-induced signaling relies on down regulation of the cytokine receptors. Down regulation of the IFNAR1 sub-unit of the Type I interferon (IFN) receptor proceeds via lysosomal receptor proteolysis, which is triggered by ubiquitination that depends on IFNAR1 serine phosphorylation. While IFN-inducible phosphorylation, ubiquitination, and degradation requires the catalytic activity of the Tyk2 Janus kinase, here we found the ligand- and Tyk2-independent pathway that promotes IFNAR1 phosphorylation, ubiquitination, and degradation when IFNAR1 is expressed at high levels. A major cellular kinase activity that is responsible for IFNAR1 phosphorylation in vitro does not depend on either ligand or Tyk2 activity. Inhibition of ligand-independent IFNAR1 degradation suppresses cell proliferation. We discuss the signaling events that might lead to ubiquitination and degradation of IFNAR1 via ligand-dependent and independent pathways and their potential physiologic significance.

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Available from: Alexander Plotnikov, Nov 20, 2014
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    • "Nevertheless, the ligands (i.e., type 1 interferons) elicit a different specific pathway leading to the downregulation of IFNAR1. This pathway is largely dependent on activities of TYK2 and JAK1 [Marijanovic et al., 2006; Liu et al., 2008]. Activated JAKs signal toward IFNAR1 downregulation via stimulating the recruitment of b‐Trcp as a result of increased serine phosphorylation within the IFNAR1 phospho‐degron [Kumar et al., 2004; Marijanovic et al., 2006]. "
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    ABSTRACT: Activation of cytokine receptor-associated Janus kinases (JAKs) mediates most, if not all, of the cellular responses to peptide hormones and cytokines. Consequently, JAKs play a paramount role in homeostasis and immunity. Members of this family of tyrosine kinases control the cytokine/hormone-induced alterations in cell gene expression program. This function is largely mediated through an ability to signal towards activation of the signal transducer and activator of transcription proteins (STAT) as well as towards some other pathways. Importantly, JAKs are also instrumental in tightly controlling the expression of associated cytokine and hormone receptors, and, accordingly, in regulating the cell sensitivity to these cytokines and hormones. This review highlights the enzymatic and non-enzymatic mechanisms of this regulation and discusses the importance of the ambidextrous nature of JAK as a key signaling node that integrates the combining the functions of forward signaling and eliminative signaling. Attention to the latter aspect of JAK function may contribute to emancipating our approaches to the pharmacologic modulation of JAKs. J. Cell. Biochem. © 2013 Wiley Periodicals, Inc.
    Preview · Article · Jan 2014 · Journal of Cellular Biochemistry
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    • "The Skip, Cullin, F-box containing complex β-TrCP E3 ubiquitin ligase mediates the ubiquitination of IFNAR1 in a phosphorylation-dependent manner, eventually designating IFNAR1 for lysosomal degradation (5). Catalytic activation of Tyk2 is required for these events but is not essential for IFNAR1 internalization (6). Conversely, it has been also reported that Tyk2 is essential for the stable cell surface expression of IFNAR1 and stabilizes IFNAR1 by its interaction in the basal condition (in the absence of ligand) (7). "
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    ABSTRACT: We have previously shown that hepatitis B virus (HBV) protein X (HBX), a regulatory protein of HBV, activates Stat1, leading to type I interferon (IFN) production. Type I IFN secreted from HBX-expressing hepatic cells enforces antiviral signals through its binding to the cognate type I IFN receptor. We therefore investigated how cells handle this detrimental situation. Interestingly, compared to Chang cells stably expressing an empty vector (Chang-Vec), Chang cells stably expressing HBX (Chang-HBX) showed lower levels of IFN-α receptor 1 (IFNAR1) protein, a subunit of type I IFN receptor. The levels of IFNAR1 transcripts detected in Chang-HBX cells were lower than the levels in Chang-Vec cells, indicating that HBX regulates IFNAR1 at the transcriptional level. Moreover, we observed that HBX induced the translocation of IFNAR1 to the cytoplasm. Consistent with these observations, HBX also downregulated Tyk2, which is required for the stable expression of IFNAR1 on the cell surface. Eventually, Chang-HBX cells consistently maintained a lower level of IFNAR1 expression and displayed no proper response to IFN-α, while Chang-Vec cells exhibited a proper response to IFN-α treatment. Taken together, we propose that HBX downregulates IFNAR1, leading to the avoidance of extracellular IFN-α signal transduction.
    Full-text · Article · Jan 2012 · International Journal of Molecular Medicine
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    • "IL-10R1 belongs to the class II cytokine receptor family that also includes type I IFN receptor subunits (reviewed in [29]). Previous studies have comprehensively unveiled that the recruitment of SCFβTrCP ubiquitin E3 ligase to type I IFN receptor serves as a convergence point of multiple signaling pathways that regulate the latter receptor's stability [33], [34], [35], [36], [37], [38], [39]. In the present study, we tested the possibility of IL-10R1 also being a target of βTrCP-mediated ubiquitination and down-regulation. "
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    ABSTRACT: Interleukin-10 (IL-10) initiates potent anti-inflammatory effects via activating its cell surface receptor, composed of IL-10R1 and IL-10R2 subunits. The level of IL-10R1 is a major determinant of the cells' responsiveness to IL-10. Here, via a series of biochemical analyses using 293T cells reconstituted with IL-10R1, we identify the latter as a novel substrate of βTrCP-containing ubiquitin E3 ligase. Within the intracellular tail of IL-10R1, a canonical ((318)DpSGFGpS) and a slightly deviated ((369)DpSGICLQEP) βTrCP recognition motif can additively recruit βTrCP in a phosphorylation-dependent manner. βTrCP recruitment leads to ubiquitination, endocytosis and degradation of IL-10R1, subsequently reducing the cellular responsiveness to IL-10. Our study uncovers a novel negative regulatory mechanism that may potentially affect IL-10 function in target cells under physiological or pathological conditions.
    Full-text · Article · Nov 2011 · PLoS ONE
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