The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response

Qiang Wang; Liyuan Huang; Ze Hong; Zhongshi Lv; Zhaomin Mao; Yijun Tang; Xiufang Kong; Senlin Li; Ye Cui; Heng Liu; Lele Zhang; Xiaojie Zhang; Lindi Jiang; Chen Wang; Qin Zhou

doi:10.1371/journal.ppat.1006264

The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response

PLoS Pathog. 2017 Mar 8;13(3):e1006264. doi: 10.1371/journal.ppat.1006264. eCollection 2017 Mar.

Authors

Qiang Wang^{1

2}, Liyuan Huang¹, Ze Hong³, Zhongshi Lv¹, Zhaomin Mao¹, Yijun Tang², Xiufang Kong⁴, Senlin Li², Ye Cui², Heng Liu², Lele Zhang², Xiaojie Zhang⁴, Lindi Jiang⁴, Chen Wang^{2

3}, Qin Zhou¹

Affiliations

¹ Division of Molecular Nephrology and the Creative Training Center for Undergraduates, the Ministry of Education Key Laboratory of Laboratory Medical Diagnostics, the School of Laboratory Medicine, Chongqing Medical University, Chongqing, China.
² State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
³ School of Life Science and Technology, China Pharmaceutical University, Jiangning District, Nanjing, China.
⁴ Department of Rheumatology, Zhongshan Hospital, Fudan University, Shanghai, China.

Abstract

The cyclic GMP-AMP synthase (cGAS), upon cytosolic DNA stimulation, catalyzes the formation of the second messenger 2'3'-cGAMP, which then binds to stimulator of interferon genes (STING) and activates downstream signaling. It remains to be elucidated how the cGAS enzymatic activity is modulated dynamically. Here, we reported that the ER ubiquitin ligase RNF185 interacted with cGAS during HSV-1 infection. Ectopic-expression or knockdown of RNF185 respectively enhanced or impaired the IRF3-responsive gene expression. Mechanistically, RNF185 specifically catalyzed the K27-linked poly-ubiquitination of cGAS, which promoted its enzymatic activity. Additionally, Systemic Lupus Erythematosus (SLE) patients displayed elevated expression of RNF185 mRNA. Collectively, this study uncovers RNF185 as the first E3 ubiquitin ligase of cGAS, shedding light on the regulation of cGAS activity in innate immune responses.

MeSH terms

Adolescent
Adult
Cells, Cultured
Female
Herpes Simplex / immunology
Herpesvirus 1, Human
Humans
Immunity, Innate / immunology*
Immunoblotting
Immunoprecipitation
Lupus Erythematosus, Systemic / immunology*
Male
Microscopy, Confocal
Middle Aged
Mitochondrial Proteins / immunology*
Nucleotidyltransferases / immunology*
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Transfection
Ubiquitin-Protein Ligases / immunology*
Young Adult

Substances

Mitochondrial Proteins
RNA, Small Interfering
RNF185 protein, human
Ubiquitin-Protein Ligases
Nucleotidyltransferases
cGAS protein, human

Grants and funding

This work was supported by grants from National Natural Science Foundation of China (81672029, 31601136, 31271563, 81572076), Ministry of Science and Technology of China (2016YFA0501800, 2016YFC1100200), and National Basic Research Program of China (2011CB944002). Dr. Qiang Wang is sponsored by Science and Technology Commission of Shanghai Municipality “Sailing Program” (16YF1413600) and China Postdoctoral Science Foundation (2016M590390). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.