Parkin Impairs Antiviral Immunity by Suppressing the Mitochondrial Reactive Oxygen Species-Nlrp3 Axis and Antiviral Inflammation

Jian Li; Chunmei Ma; Fei Long; Dongxue Yang; Xue Liu; Yingchao Hu; Chunyan Wu; Bingwei Wang; Min Wang; Yunzi Chen; Genyan Liu; Paul N Moynagh; Jiawei Zhou; Tao Peng; Shuo Yang

doi:10.1016/j.isci.2019.06.008

Parkin Impairs Antiviral Immunity by Suppressing the Mitochondrial Reactive Oxygen Species-Nlrp3 Axis and Antiviral Inflammation

iScience. 2019 Jun 28:16:468-484. doi: 10.1016/j.isci.2019.06.008. Epub 2019 Jun 11.

Authors

Jian Li¹, Chunmei Ma¹, Fei Long², Dongxue Yang¹, Xue Liu¹, Yingchao Hu¹, Chunyan Wu¹, Bingwei Wang³, Min Wang⁴, Yunzi Chen¹, Genyan Liu⁴, Paul N Moynagh⁵, Jiawei Zhou⁶, Tao Peng⁷, Shuo Yang⁸

Affiliations

¹ Department of Immunology, Key Laboratory of Immunological Environment and Disease, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China.
² Laboratory of Viral Immunology, State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China.
³ Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, China.
⁴ Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
⁵ Maynooth University Human Health Research Institute, Department of Biology, National University of Ireland Maynooth, Maynooth, Ireland; Centre for Experimental Medicine, Queen's University Belfast, Belfast, UK.
⁶ Institute of Neuroscience, State Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
⁷ Laboratory of Viral Immunology, State Key Laboratory of Respiratory Disease, Sino-French Hoffmann Institute, Guangzhou Medical University, Guangzhou, China. Electronic address: peng_tao@gibh.ac.cn.
⁸ Department of Immunology, Key Laboratory of Immunological Environment and Disease, State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, China. Electronic address: shuoyang@njmu.edu.cn.

Abstract

Although mitochondria are known to be involved in host defense against viral infection, the physiological role of mitophagy, a crucial mechanism for maintaining mitochondrial homeostasis, in antiviral immunity remains poorly defined. Here, we show that Parkin, a central player in mitophagy, has a vital function in regulating host antiviral responses. Parkin-knockout mice exhibit improved viral clearance and survival after viral infection. However, Parkin deficiency does not affect antiviral signaling and interferon production. Instead, Parkin deficiency augments innate antiviral inflammation by enhancing mitochondrial ROS (mtROS)-mediated NLRP3 inflammasome activation and promoting viral clearance. Loss of NLRP3 can reverse the enhanced antiviral responses in Parkin knockout mice. Furthermore, we find that Parkin expression is downregulated in peripheral blood mononuclear cells of patients infected with virus. Collectively, our results suggest that Parkin plays an important role in antiviral immunity by controlling mtROS-NLRP3 axis-mediated inflammation. These findings provide physiological insight of the importance of mitophagy in regulating host antiviral response.

Keywords: Biochemistry; Biological Sciences; Cell Biology; Genetics; Immunology; Molecular Biology.