title: Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1.
abstract: An ability to sense pathogens by a number of specialized cell types including the dendritic cells plays a central role in host's defenses. Activation of these cells through the stimulation of the pathogen-recognition receptors induces the production of a number of cytokines including Type I interferons (IFNs) that mediate the diverse mechanisms of innate immunity. Type I IFNs interact with the Type I IFN receptor, composed of IFNAR1 and IFNAR2 chains, to mount the host defense responses. However, at the same time, Type I IFNs elicit potent anti-proliferative and pro-apoptotic effects that could be detrimental for IFN-producing cells. Here, we report that the activation of p38 kinase in response to pathogen-recognition receptors stimulation results in a series of phosphorylation events within the IFNAR1 chain of the Type I IFN receptor. This phosphorylation promotes IFNAR1 ubiquitination and accelerates the proteolytic turnover of this receptor leading to an attenuation of Type I IFN signaling and the protection of activated dendritic cells from the cytotoxic effects of autocrine or paracrine Type I IFN. In this paper we discuss a potential role of this mechanism in regulating the processes of innate immunity.
authors.affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Juan
authors.initials: J
authors.lastname: Qian
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Huangfu
authors.forename: Jianghuai
authors.initials: J
authors.lastname: Liu
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carbone
authors.forename: N Adrian
authors.initials: NA
authors.lastname: Leu
authors.forename: Darren P
authors.initials: DP
authors.lastname: Baker
authors.forename: Serge Y
authors.initials: SY
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D007370:Interferon Type I / Q000276:immunology; D051379:Mice; D010766:Phosphorylation; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D054875:Ubiquitination / Q000276:immunology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000276:immunology / Q000378:metabolism
chemical_list: C507964:IFNAR1 protein, human; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D048051:p38 Mitogen-Activated Protein Kinases