Mammalian casein kinase 1α and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling

Jianghuai Liu, Lucas P. Carvalho, Sabyasachi Bhattacharya, Christopher J. Carbone, K. G.Suresh Kumar, N. Adrian Leu, Peter M. Yau, Robert G.K. Donald, Mitchell J. Weiss, Darren P. Baker, K. John McLaughlin, Phillip Scott, Serge Y. Fuchs

Research output: Contribution to journalArticlepeer-review

Abstract

Phosphorylation of the degron of the IFNAR1 chain of the type I interferon (IFN) receptor triggers ubiquitination and degradation of this receptor and, therefore, plays a crucial role in negative regulation of IFN-α/β signaling. Besides the IFN-stimulated and Jak activity-dependent pathways, a basal ligand-independent phosphorylation of IFNAR1 has been described and implicated in downregulating IFNAR1 in response to virus-induced endoplasmic reticulum (ER) stress. Here we report purification and characterization of casein kinase 1α (CK1α) as a bona fide major IFNAR1 kinase that confers basal turnover of IFNAR1 and cooperates with ER stress stimuli to mediate phosphorylation-dependent degradation of IFNAR1. Activity of CK1α was required for phosphorylation and downregulation of IFNAR1 in response to ER stress and viral infection. While many forms of CK1 were capable of phosphorylating IFNAR1 in vitro, human CK1α and L-CK1 produced by the protozoan Leishmania major were also capable of increasing IFNAR1 degron phosphorylation in cells. Expression of leishmania CK1 in mammalian cells stimulated the phosphorylation-dependent downregulation of IFNAR1 and attenuated its signaling. Infection of mammalian cells with L. major modestly decreased IFNAR1 levels and attenuated cellular responses to IFN-α in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and type I IFN signaling.

Original languageEnglish (US)
Pages (from-to)6401-6412
Number of pages12
JournalMolecular and cellular biology
Volume29
Issue number24
DOIs
StatePublished - Dec 2009

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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