title: Mammalian casein kinase 1alpha and its leishmanial ortholog regulate stability of IFNAR1 and type I interferon signaling.
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-alpha/beta 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 1alpha (CK1alpha) 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 CK1alpha 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 CK1alpha 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-alpha in vitro. We propose a role for mammalian and parasite CK1 enzymes in regulating IFNAR1 stability and type I IFN signaling.
authors.affiliation: Department of Animal Biology, University of Pennsylvania, 380 S. University Avenue, Hill 316, Philadelphia, PA 19104-4539, USA.
authors.forename: Jianghuai
authors.initials: J
authors.lastname: Liu
authors.forename: Lucas P
authors.initials: LP
authors.lastname: Carvalho
authors.forename: Sabyasachi
authors.initials: S
authors.lastname: Bhattacharya
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carbone
authors.forename: K G Suresh
authors.initials: KG
authors.lastname: Kumar
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.forename: Peter M
authors.initials: PM
authors.lastname: Yau
authors.forename: Robert G K
authors.initials: RG
authors.lastname: Donald
authors.forename: Mitchell J
authors.initials: MJ
authors.lastname: Weiss
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: K John
authors.initials: KJ
authors.lastname: McLaughlin
authors.forename: Phillip
authors.initials: P
authors.lastname: Scott
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D048128:Casein Kinase Ialpha / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007370:Interferon Type I / Q000378:metabolism*; D018320:Leishmania major / Q000201:enzymology*; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D007370:Interferon Type I; D020033:Protein Isoforms; D015800:Protozoan Proteins; D034741:RNA, Small Interfering; D053633:Receptor, Interferon alpha-beta; D048128:Casein Kinase Ialpha