Role of p38 Protein Kinase in the Ligand-independent Ubiquitination and Down-regulation of the IFNAR1 Chain of Type I Interferon Receptor
Autor: | Christos Tzimas, Constantinos Koumenis, Darren P. Baker, J. Alan Diehl, Juan Qian, Sabyasachi Bhattacharya, Serge Y. Fuchs |
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Rok vydání: | 2011 |
Předmět: |
Down-Regulation
Receptor Interferon alpha-beta Mitogen-activated protein kinase kinase Ligands p38 Mitogen-Activated Protein Kinases Biochemistry MAP2K7 Mice Animals Humans ASK1 c-Raf Phosphorylation Protein Kinase Inhibitors Molecular Biology biology MAP kinase kinase kinase Protein Stability Cyclin-dependent kinase 2 Ubiquitination Interferon-alpha Interferon-beta Vesiculovirus Cell Biology Gene Knockdown Techniques Cancer research biology.protein Cyclin-dependent kinase 9 Janus kinase HeLa Cells Signal Transduction |
Zdroj: | Journal of Biological Chemistry |
ISSN: | 0021-9258 |
Popis: | Phosphorylation-dependent ubiquitination and degradation of the IFNAR1 chain of type I interferon (IFN) receptor is a robust and specific mechanism that limits the magnitude and duration of IFNα/β signaling. Besides the ligand-inducible IFNAR1 degradation, the existence of an “inside-out” signaling that accelerates IFNAR1 turnover in the cells undergoing the endoplasmic reticulum (ER) stress and activated unfolded protein responses has been recently described. The latter pathway does not require either presence of ligands (IFNα/β) or catalytic activity of Janus kinases (JAK). Instead, this pathway relies on activation of the PKR-like ER kinase (PERK) and ensuing specific priming phosphorylation of IFNAR1. Here, we describe studies that identify the stress activated p38 protein kinase as an important regulator of IFNAR1 that acts downstream of PERK. Results of the experiments using pharmacologic p38 kinase inhibitors, RNA interference approach, and cells from p38α knock-out mice suggest that p38 kinase activity is required for priming phosphorylation of IFNAR1 in cells undergoing unfolded protein response. We further demonstrate an important role of p38 kinase in the ligand-independent stimulation of IFNAR1 ubiquitination and degradation and ensuing attenuation of IFNα/β signaling and anti-viral defenses. We discuss the distinct importance of p38 kinase in regulating the overall responses to type I IFN in cells that have been already exposed to IFNα/β versus those cells that are yet to encounter these cytokines. |
Databáze: | OpenAIRE |
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