FKBP5 Regulates RIG-I-Mediated NF-κB Activation and Influenza A Virus Infection.

Wenzhuo Hao,Lingyan Wang,Shitao Li

doi:10.3390/v12060672

Abstract

Influenza A virus (IAV) is a highly transmissible respiratory pathogen and is a constant threat to global health with considerable economic and social impact. Influenza viral RNA is sensed by host pattern recognition receptors (PRRs), such as the Toll-like receptor 7 (TLR7) and retinoic acid-inducible gene I (RIG-I). The activation of these PRRs instigates the interferon regulatory factor (IRF) and nuclear factor kappa B (NF-κB) signaling pathways that induce the expression of interferon-stimulated genes (ISGs) and inflammatory genes. FK506-binding protein 5 (FKBP5) has been implied in the IκBα kinase (IKK) complex. However, the role of FKBP5 in the RIG-I signaling and IAV infection is not well elucidated. Here, we demonstrate that the knockout of FKBP5 increases IAV infection. Furthermore, FKBP5 binds IKKα, which is critical for RIG-I-induced innate immune responses and ISG expression. Taken together, FKBP5 is a novel anti-influenza host factor that restricts IAV infection by the activation of RIG-I-mediated NF-κB signaling.

Highlights

Influenza A virus (IAV) is a negative, single-stranded RNA virus that belongs to the Orthomyxoviridae family
A single guide RNA (sgRNA) was cloned into the lentiCRISPR v2 containing Cas9 and transfected into HEK293 cells
Upon the engagement with viral RNA, retinoic acid-inducible gene I (RIG-I) activates signaling cascades that lead to the induction of typereceptors

Summary

Introduction

Influenza A virus (IAV) is a negative, single-stranded RNA virus that belongs to the Orthomyxoviridae family. RIG-I is a cytosolic RNA sensor that binds IAV RNA. The binding of RNA induces conformational change and several post-translation modifications, such as K63-linked polyubiquitination, which leads to the oligomerization of RIG-I. The oligomerized RIG-I further induces the oligomerization of the mitochondrial antiviral signaling protein (MAVS, known as CARDIF, IPS1, and VISA). The oligomerized MAVS acts as a signaling platform by recruitment of IKK and TANK-binding kinase 1 (TBK1). IKK and TBK1 activate the transcription factors, NF-κB and IRF, respectively. NF-κB and IRF translocate to the nucleus and form transcriptional complexes to activate type I interferon (IFN) expression. The type I IFN acts as a master cytokine that activates hundreds of interferon-stimulated genes, which in turn inhibit

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