Non-Canonical Role of IKKα in the Regulation of STAT1 Phosphorylation in Antiviral Signaling.

Fei Xing,Tadaatsu Imaizumi,Yuko Shiba,Hidemi Yoshida,Ryo Hayakari,Tomoh Matsumiya,Martin E Rottenberg

doi:10.1371/journal.pone.0168696

Fei Xing, Tadaatsu Imaizumi + Show 5 more

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https://doi.org/10.1371/journal.pone.0168696

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Journal: PloS one	Publication Date: Dec 19, 2016
License type: CC BY 4.0

Affiliation: Hirosaki University

Abstract

Non-self RNA is recognized by retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs), inducing type I interferons (IFNs). Type I IFN promotes the expression of IFN-stimulated genes (ISGs), which requires the activation of signal transducer and activator of transcription-1 (STAT1). We previously reported that dsRNA induced STAT1 phosphorylation via a type I IFN-independent pathway in addition to the well-known type I IFN-dependent pathway. IκB kinase α (IKKα) is involved in antiviral signaling induced by dsRNA; however, its role is incompletely understood. Here, we explored the function of IKKα in RLR-mediated STAT1 phosphorylation. Silencing of IKKα markedly decreased the level of IFN-β and STAT1 phosphorylation inHeH response to dsRNA. However, the inhibition of IKKα did not alter the RLR signaling-mediated dimerization of interferon responsive factor 3 (IRF3) or the nuclear translocation of nuclear factor-κB (NFκB). These results suggest a non-canonical role of IKKα in RLR signaling. Furthermore, phosphorylation of STAT1 was suppressed by IKKα knockdown in cells treated with a specific neutralizing antibody for the type I IFN receptor (IFNAR) and in IFNAR-deficient cells. Collectively, the dual regulation of STAT1 by IKKα in antiviral signaling suggests a role for IKKα in the fine-tuning of antiviral signaling in response to non-self RNA.

Highlights

Microorganism invasion in a vertebrate host is initially recognized by pattern recognition receptors (PRRs), resulting in the activation of the innate immune system [1]
We previously reported that transfection of polyinosinic-polycytidylic acid, a synthetic viral double-stranded RNA (dsRNA) analog, activates RIG-I-like receptors (RLRs) signaling in HeLa cells [20]
Activation of signal transducer and activator of transcription-1 (STAT1) is required to induce IFN-stimulated genes (ISGs) [21]; we examined the role of IKKs in the RLR signaling-mediated STAT1 phosphorylation

Summary

Introduction

Microorganism invasion in a vertebrate host is initially recognized by pattern recognition receptors (PRRs), resulting in the activation of the innate immune system [1]. RIG-I-like receptors (RLRs) are PRRs that recognize non-self RNA in the cytoplasm. Following the recognition of non-self RNA, RIG-I undergoes a conformational change to interact with a downstream adaptor molecule, mitochondrial antiviral signaling protein (MAVS) [2], which is known as virus-induced signaling adaptor (VISA) [3], interferon (IFN)-β promoter stimulator-1 (IPS-1) [4], or caspase activation and recruitment domain adaptor inducing IFN-β (Cardif) [5]. MAVS activates downstream signaling molecules to produce type I IFNs [6]. Type I IFNs are essential for mounting a robust host response against viral infection.

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