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. We have previously observed and reported that the activation of unfolded protein responses during infection with some viruses such as vesicular stomatitis virus and hepatitis C virus compromises the cellular responses to the cytokines that belong to family of Type I interferons (IFNα/β). These effects apparently rely on the activation of a specific protein kinase termed PERK that transduces signals from unfolded proteins to accelerate phosphorylation-dependent degradation of the IFNα/β receptor. Here we found that the same pathway can be PERK-independent and can be stimulated by signaling induced in the specialized cells (e.g. dendritic cells that produce IFNα/β), which recognize pathogens (e.g. viruses). This work delineates a mechanism by which the degradation of IFNα/β receptor is accelerated. Our studies also highlight the importance of this mechanism for limiting the magnitude and the duration of IFNα/β signaling and maintaining the survival of IFN-producing dendritic cells.