Excerpt: Interferon (IFN) regulatory factor 7 (IRF7) is phosphorylated and activated in response to pathogenic infections for production of type I IFN

Ning, Shunbin

Wang, Ling

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East Tennessee State University

East Tennessee State University Digital Commons @ East Tennessee State University ETSU Faculty Works Faculty Works 1-1-2017 Identification of PP1 as the First Phosphatase for IRF7 Shunbin Ning East Tennessee State University, nings1@etsu.edu Ling Wang East Tennessee State University, wangl3@etsu.edu Follow this and additional works at: https://dc.etsu.edu/etsu-works  Part of the Internal Medicine Commons Citation Information Ning, Shunbin; and Wang, Ling. 2017. Identification of PP1 as the First Phosphatase for IRF7. Journal of Cell Signaling. Vol.2(2). 146-146. https://doi.org/10.18632/oncotarget.16385 ISSN: 2576-1471 This Article is brought to you for free and open access by the Faculty Works at Digital Commons @ East Tennessee State University. It has been accepted for inclusion in ETSU Faculty Works by an authorized administrator of Digital Commons @ East Tennessee State University. For more information, please contact digilib@etsu.edu. Identification of PP1 as the First Phosphatase for IRF7 Copyright Statement © 2017 Ning S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Creative Commons License This work is licensed under a Creative Commons Attribution 4.0 License. This article is available at Digital Commons @ East Tennessee State University: https://dc.etsu.edu/etsu-works/6527 Identification of PP1 as the First Phosphatase for IRF7Shunbin Ning1,2, Ling Wang1,2*1Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, USA2Department of Internal Medicine, Quillen College of Medicine, East Tennessee State University, Johnson City, USA*Corresponding author: Ling Wang, Center of Excellence for Inflammation, Infectious Diseases and Immunity, Quillen College of Medicine, East Tennessee StateUniversity, Johnson City, USA, Tel: 423-439-8063; E-mail: wangl3@etsu.eduReceived date: March 13, 2017; Accepted date: April 11, 2017; Published date: April 19, 2017Copyright: © 2017 Ning S. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,distribution, and reproduction in any medium, provided the original author and source are credited.CommentaryInterferon (IFN) regulatory factor 7 (IRF7) is phosphorylated andactivated in response to pathogenic infections for production of type IIFNs. The IFN production has to be turned off soon after infection.While there are a panel of kinases have been identified for IRF7phosphorylation, no phosphatase has been reported for IRF7dephosphorylation that may play a pivotal role in turning off IFNproduction. We have recently addressed this critical question byidentification of protein phosphatase 1 (PP1) as the first phosphatasefor IRF7.Main content: The host innate immune system defends againstinvading pathogens initially by triggering signaling pathways mediatedby the transmembrane receptors TLRs [1], and cytoplasmic receptorsthat include RLRs [2,3], NLRs [4], cGAS [5,6], IFI16 [7], DDX41 [8,9],DHX9/36 [10,11], RNA polymerase III [12], TRIM5α [13], ISG56 [14],LRRFIP1 [15], MRE11 [16], amongst others. Interferon (IFN)regulatory factor 7 (IRF7) is phosphorylated and activated downstreamof many of these innate immune pathways for induction of IFN-I geneexpression (especially IFNαs) [17]. The innate immune system alsocomprises of lymphocytes-mediated epigenetic memory, whichdefends reinfection and involves ATF7-mediated chromatin regulation[18,19].IRF7 is required not only for IFN priming at early stage, but also forIFN amplification at later stages when robust IFN-I productiondepends on a positive regulatory circuit between IRF7 and IFN-I[20-22]. This robust reaction is turned off soon after infection undernormal physiological conditions, but excessive production of IFN-I isfatal to the cell. Thus, regulation of IRF7 phosphorylation is ofparamount importance for controlling antiviral innate immunity.However, no phosphatase for negative regulation of IRF7phosphorylation and activity has been reported.In our recent study [23], we have identified a conserved proteinphosphatase 1 (PP1)-binding motif in human and mouse IRF7proteins, and shown that PP1 physically interacts with IRF7.Exogenous expression of PP1 subunits (PP1α, β or γ) ablates IKKε-stimulated IRF7 phosphorylation and dramatically attenuates IRF7transcriptional activity. Inhibition of PP1 activity significantlyincreases IRF7 phosphorylation and IRF7-mediated IFNα productionin response to NDV infection or Toll-like receptor 7 (TLR7) challenge,leading to impaired viral replication. In addition, IFN treatment, TLRchallenges and viral infection induce PP1 expression.Figure 1: PP1 abrogates IRF7-mediated type I IFN response inantiviral immunity. IRF7 is phosphorylated by IKKs or IRAK1downstream of TLR signaling pathways in response to viralinfection. PP1 targets IRF7 for dephosphorylation and attenuatestype I IFN production in these signaling pathways. Also, PP1promotes IL6 production. In addition, IFN treatment, TLRchallenges and viral infection induce PP1 expression.Correspondingly, we have identified IFN-responsive elements andIRF-binding motifs in the PP1 gene promoters, and thetranscriptional regulation is currently under investigated.Our results are the first to identify PP1 as a phosphatase that targetskey activating phosphorylation sites of IRF7, attenuating its activityand blocking the IFN-I response during viral infection (Figure 1).Thus, our study has addressed an important knowledge gap regardingIRF7-mediated IFN-I innate immune response, and has broadsignificance in IFN-mediated antiviral innate immunity and IRF7-mediated pathogenesis [17]. In future follow-up studies, we willvalidate our findings in in vivo systems, and develop strategies tocontrol PP1 phosphatase activity during viral infection for potentialclinical interventions.Ning et al., J Cell Signal 2017, 2:2Commentary Open AccessJ Cell Signal, an open access journal Volume 2 • Issue 2 • 146Journal of Cell SignalingISSN: 2576-1471Journal of Cell SignalingReferences1. Kawai T, Akira S (2010) The role of pattern-recognition receptors ininnate immunity: update on Toll-like receptors. Nat Immunol 11:373-384.2. Rehwinkel J, Reis e Sousa C (2010) RIGorous detection: exposing virusthrough RNA sensing. Science 327: 284-286.3. Hornung V, Latz E (2010) Intracellular DNA recognition. Nat RevImmunol 10: 123-130.4. Sha W, Mitoma H, Hanabuchi S, Bao M, Weng L, et al. (2014) HumanNLRP3 inflammasome senses multiple types of bacterial RNAs. Proc NatlAcad Sci U S A 111: 16059-16064.5. 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Identification of PP1 as the First Phosphatase for IRF7

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Identification of PP1 as the First Phosphatase for IRF7

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