Pathogen Recognition Receptor Signaling Accelerates Phosphorylation-Dependent Degradation of IFNAR1

• DOI: 10.1371/journal.ppat.1002065
• Publication Date: 2011-06-17T21:16:21Z
• Authors: Juan Qian; Hui Zheng; Wei-Chun HuangFu; Jianghuai Liu; Christopher J. Ca...; N. Adrian Leu; Darren P. Baker; Serge Y. Fuchs
• Keywords: 0303 health sciences; QH301-705.5; Ubiquitination; Dendritic Cells; Receptor, Interferon alpha-beta; RC581-607; p38 Mitogen-Activated Protein Kinases; Immunity, Innate; Cell Line; 3. Good health; Mice; 03 medical and health sciences; Interferon Type I; Animals; Humans; Immunologic diseases. Allergy; Biology (General); Phosphorylation; Research Article; Signal Transduction

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.