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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: 2.28). 04/2008; 367(2):388-93. DOI: 10.1016/j.bbrc.2007.12.137
Source: PubMed

ABSTRACT 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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    • "Like the TCR and CD4, the IFNRs, particularly IFNGR1, are recruited to lipid rafts upon activation from where they are endocytosed (Claudinon et al., 2007). Recently, a ligand-independent mechanism of IFNAR internalisation and degradation has been reported (Liu et al., 2008). Although phosphorylation and ubiquitination are required, it requires the activity of an as yet unidentified kinase distinct from TYK2. "
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    • "However, recent evidence suggested the existence of a ligand-and Jak-independent pathway that controls stability of IFNAR1 in a phosphorylation-dependent manner. The importance of the latter pathway remained unclear as it was largely observed under the conditions of IFNAR1 overexpression (Liu et al., 2008). Here we report that this pathway is triggered by activation of the ER stress in a manner that requires function of PERK. "
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