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

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

doi:10.3389/fimmu.2020.01926

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

Front Immunol. 2020 Sep 2:11:1926. doi: 10.3389/fimmu.2020.01926. eCollection 2020.

Authors

Lang Bu¹, Huan Wang², Panpan Hou¹, Shuting Guo³, Miao He¹, Jingshu Xiao¹, Ping Li¹, Yongheng Zhong¹, Penghui Jia¹, Yuanyuan Cao⁴, Guanzhan Liang¹, Chenwei Yang¹, Lang Chen³, Deyin Guo¹, Chun-Mei Li¹

Affiliations

¹ MOE Key Laboratory of Tropical Disease Control, the Infection and Immunity Center (TIIC), School of Medicine, Sun Yat-sen University, Shenzhen, China.
² Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
³ Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, China.
⁴ School of Basic Medical Sciences, Anhui Medical University, Hefei, China.

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.

Keywords: MDA5; RIG-I; innate immunity; mitophagy; parkin; polyubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

A549 Cells
Animals
Chlorocebus aethiops
DEAD Box Protein 58 / metabolism*
HEK293 Cells
Host-Pathogen Interactions
Humans
Hydrazones / pharmacology
Immunity, Innate* / drug effects
Interferon Type I / metabolism
Interferon-Induced Helicase, IFIH1 / metabolism*
Mice
Mitochondria / drug effects
Mitochondria / enzymology
Mitochondria / immunology*
Mitochondria / virology
Mitophagy
Protein Kinases / metabolism
RAW 264.7 Cells
Receptors, Immunologic / metabolism*
Sendai virus / genetics
Sendai virus / immunology*
Sendai virus / pathogenicity
THP-1 Cells
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination
Uncoupling Agents / pharmacology
Vero Cells
Vesiculovirus / genetics
Vesiculovirus / immunology*
Vesiculovirus / pathogenicity

Substances

Hydrazones
Interferon Type I
Receptors, Immunologic
Uncoupling Agents
carbonyl 3-chlorophenylhydrazone
Ubiquitin-Protein Ligases
parkin protein
Protein Kinases
PTEN-induced putative kinase
RIGI protein, human
IFIH1 protein, human
DEAD Box Protein 58
Interferon-Induced Helicase, IFIH1