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Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1.

Qian J, Zheng H, Huangfu WC, Liu J, Carbone CJ, Leu NA, Baker DP, Fuchs SY - PLoS Pathog. (2011)

Bottom Line: However, at the same time, Type I IFNs elicit potent anti-proliferative and pro-apoptotic effects that could be detrimental for IFN-producing cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

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Pathogen recognition receptor signaling induces p38 kinase-dependent priming phosphorylation of IFNAR1.(A) KR-2 cells were treated with CpG (10 µM for 30 min) or with HSV (5 MOI for 90 min). The phosphorylation and levels of IFNAR1 were detected after IFNAR1 immunoprecipitation using the indicated antibodies. The levels and activity of p38 kinase in WCL were also analyzed. (B) U937 cells were untreated or treated with UV-inactivated HSV (MOI 5), CpG (10 µM) or LPS (10 µg/mL) for 1 h. The phosphorylation and levels of IFNAR1 were analyzed by IP-IB using the indicated antibodies. (C) U937 cells were pre-treated with inhibitors of JNK (SP600125, 10 µM) or p38 kinase (SB203580, 10 µM) for 1 h and then treated with LPS (10 µg/ml for 1 h) and analyzed as shown in panel B. (D) U937 cells were untreated or pre-treated with the p38 kinase inhibitor SB203580 (10 µM for 1 h) and then treated with the indicated PRR agonists or UV-inactivated HSV (MOI 1), or UV-inactivated VSV (MOI 1) for 1 h and then analyzed as depicted in panel B.
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ppat-1002065-g005: Pathogen recognition receptor signaling induces p38 kinase-dependent priming phosphorylation of IFNAR1.(A) KR-2 cells were treated with CpG (10 µM for 30 min) or with HSV (5 MOI for 90 min). The phosphorylation and levels of IFNAR1 were detected after IFNAR1 immunoprecipitation using the indicated antibodies. The levels and activity of p38 kinase in WCL were also analyzed. (B) U937 cells were untreated or treated with UV-inactivated HSV (MOI 5), CpG (10 µM) or LPS (10 µg/mL) for 1 h. The phosphorylation and levels of IFNAR1 were analyzed by IP-IB using the indicated antibodies. (C) U937 cells were pre-treated with inhibitors of JNK (SP600125, 10 µM) or p38 kinase (SB203580, 10 µM) for 1 h and then treated with LPS (10 µg/ml for 1 h) and analyzed as shown in panel B. (D) U937 cells were untreated or pre-treated with the p38 kinase inhibitor SB203580 (10 µM for 1 h) and then treated with the indicated PRR agonists or UV-inactivated HSV (MOI 1), or UV-inactivated VSV (MOI 1) for 1 h and then analyzed as depicted in panel B.

Mentions: One possibility is that such a signaling pathway could be initiated by the recognition of pathogen patterns within inactivated HSV. HSV was reported to activate Toll like receptors (TLR), including TLR9, via viral genomic DNA [43], [44] as well as TLR2 via an unidentified molecular structure on the virion [45]. While we failed to detect an increase in priming or degron phosphorylation of IFNAR1 in KR-2 cells upon treatment with an activator of TLR2 muramyl dipeptide (MDP, data not shown), such phosphorylation was readily observed when KR-2 cells were treated with HSV or with TLR9 inducer CpG (Figure 5A). Whereas these results do not prove or disprove the participation of specific TLR in IFNAR1 phosphorylation mediated by HSV, they indicate a possibility that the stimulation of PRR signaling in general might lead to the same result.


Pathogen recognition receptor signaling accelerates phosphorylation-dependent degradation of IFNAR1.

Qian J, Zheng H, Huangfu WC, Liu J, Carbone CJ, Leu NA, Baker DP, Fuchs SY - PLoS Pathog. (2011)

Pathogen recognition receptor signaling induces p38 kinase-dependent priming phosphorylation of IFNAR1.(A) KR-2 cells were treated with CpG (10 µM for 30 min) or with HSV (5 MOI for 90 min). The phosphorylation and levels of IFNAR1 were detected after IFNAR1 immunoprecipitation using the indicated antibodies. The levels and activity of p38 kinase in WCL were also analyzed. (B) U937 cells were untreated or treated with UV-inactivated HSV (MOI 5), CpG (10 µM) or LPS (10 µg/mL) for 1 h. The phosphorylation and levels of IFNAR1 were analyzed by IP-IB using the indicated antibodies. (C) U937 cells were pre-treated with inhibitors of JNK (SP600125, 10 µM) or p38 kinase (SB203580, 10 µM) for 1 h and then treated with LPS (10 µg/ml for 1 h) and analyzed as shown in panel B. (D) U937 cells were untreated or pre-treated with the p38 kinase inhibitor SB203580 (10 µM for 1 h) and then treated with the indicated PRR agonists or UV-inactivated HSV (MOI 1), or UV-inactivated VSV (MOI 1) for 1 h and then analyzed as depicted in panel B.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3111542&req=5

ppat-1002065-g005: Pathogen recognition receptor signaling induces p38 kinase-dependent priming phosphorylation of IFNAR1.(A) KR-2 cells were treated with CpG (10 µM for 30 min) or with HSV (5 MOI for 90 min). The phosphorylation and levels of IFNAR1 were detected after IFNAR1 immunoprecipitation using the indicated antibodies. The levels and activity of p38 kinase in WCL were also analyzed. (B) U937 cells were untreated or treated with UV-inactivated HSV (MOI 5), CpG (10 µM) or LPS (10 µg/mL) for 1 h. The phosphorylation and levels of IFNAR1 were analyzed by IP-IB using the indicated antibodies. (C) U937 cells were pre-treated with inhibitors of JNK (SP600125, 10 µM) or p38 kinase (SB203580, 10 µM) for 1 h and then treated with LPS (10 µg/ml for 1 h) and analyzed as shown in panel B. (D) U937 cells were untreated or pre-treated with the p38 kinase inhibitor SB203580 (10 µM for 1 h) and then treated with the indicated PRR agonists or UV-inactivated HSV (MOI 1), or UV-inactivated VSV (MOI 1) for 1 h and then analyzed as depicted in panel B.
Mentions: One possibility is that such a signaling pathway could be initiated by the recognition of pathogen patterns within inactivated HSV. HSV was reported to activate Toll like receptors (TLR), including TLR9, via viral genomic DNA [43], [44] as well as TLR2 via an unidentified molecular structure on the virion [45]. While we failed to detect an increase in priming or degron phosphorylation of IFNAR1 in KR-2 cells upon treatment with an activator of TLR2 muramyl dipeptide (MDP, data not shown), such phosphorylation was readily observed when KR-2 cells were treated with HSV or with TLR9 inducer CpG (Figure 5A). Whereas these results do not prove or disprove the participation of specific TLR in IFNAR1 phosphorylation mediated by HSV, they indicate a possibility that the stimulation of PRR signaling in general might lead to the same result.

Bottom Line: However, at the same time, Type I IFNs elicit potent anti-proliferative and pro-apoptotic effects that could be detrimental for IFN-producing cells.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH