The Ubiquitin E3 Ligase Parkin Inhibits Innate Antiviral Immunity Through K48-Linked Polyubiquitination of RIG-I and MDA5.

Lang Bu,Ping Li,Lang Chen,Chun-Mei Li,Miao He,Panpan Hou,Yuanyuan Cao,Shuting Guo,Guanzhan Liang,Deyin Guo,Penghui Jia,Huan Wang,Chenwei Yang,Jingshu Xiao,Yongheng Zhong

doi:10.3389/fimmu.2020.01926

Abstract

Innate immunity is the first-line defense against antiviral or antimicrobial infection. RIG-I and MDA5, which mediate the recognition of pathogen-derived nucleic acids, are essential for production of type I interferons (IFN). Here, we identified mitochondrion depolarization inducer carbonyl cyanide 3-chlorophenylhydrazone (CCCP) inhibited the response and antiviral activity of type I IFN during viral infection. Furthermore, we found that the PTEN-induced putative kinase 1 (PINK1) and the E3 ubiquitin-protein ligase Parkin mediated mitophagy, thus negatively regulating the activation of RIG-I and MDA5. Parkin directly interacted with and catalyzed the K48-linked polyubiquitination and subsequent degradation of RIG-I and MDA5. Thus, we demonstrate that Parkin limits RLR-triggered innate immunity activation, suggesting Parkin as a potential therapeutic target for the control of viral infection.

Highlights

The self- vs. non-self-recognition by the innate immune system has been first reported by Charles Alderson Janeway in 1989 [1]
In order to study the possible regulatory effects of mitophagy on innate immunity, we first tested the effect of the carbonyl cyanide 3-chlorophenylhydrazone (CCCP) on mitochondria depolarization
Luciferase assays showed that CCCP inhibited the Sendai virus (SeV)-induced activation of IFNB1 promoter reporter and interferon-stimulating regulatory element (ISRE) promoter reporter containing IRF3-responsive positive regulatory domains (PRD) III and I, but did not inhibit the activation of nuclear factor-κB (NF-κB) promoter reporter (Figure 1B)

Summary

Introduction

The self- vs. non-self-recognition by the innate immune system has been first reported by Charles Alderson Janeway in 1989 [1]. MDA5 and RIG-I both bind to dsRNA [7] They all have a DExD/H box RNA helicase domain that can detect viral RNA and a C-terminal RNA binding domain (CTD). Both RIG-I and MDA5 contain two caspase activation and recruitment domains (CARDs) in N-terminal region, whereas LGP2 lacks the CARD domains. When the RIG-I or MDA5 recognizes the viral dsRNA, it exposes the N-terminal CARD domains, Parkin Inhibits Innate Immunity which interact with the CARD domain of the mitochondrial antiviral signaling protein (MAVS) [8]. NFκB and IRFs translocate into the nucleus, where they activate the innate immunity and promote the expression of proinflammatory cytokines and type I IFNs [10]

Methods

Results

Conclusion