Role of TOMM34 on NF-κB activation-related hyperinflammation in severely ill patients with COVID-19 and influenzaResearch in context
Qiwen Shi,
Pengfei Zhang,
Qingtao Hu,
Tianxin Zhang,
Ruixia Hou,
Shengxiang Yin,
Yilin Zou,
Fenghua Chen,
Shuang Jiao,
Lanlan Si,
Bangjin Zheng,
Yichao Chen,
Tingzhu Zhan,
Yongxiang Liu,
Wenting Zhu,
Nan Qi
Affiliations
Qiwen Shi
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China
Pengfei Zhang
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Qingtao Hu
State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
Tianxin Zhang
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Ruixia Hou
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China
Shengxiang Yin
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Yilin Zou
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Fenghua Chen
State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
Shuang Jiao
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Lanlan Si
State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China
Bangjin Zheng
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Yichao Chen
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China
Tingzhu Zhan
Collaborative Innovation Center of Yangtze River Delta Region Green Pharmaceuticals, College of Pharmaceutical Sciences, Zhejiang University of Technology, Hangzhou, 310014, China
Yongxiang Liu
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China; Corresponding author.
Wenting Zhu
Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China; Corresponding author.
Nan Qi
State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China; Guangzhou National Laboratory, Guangzhou International Bio-Island, Guangzhou, 510005, China; Corresponding author.State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou 510120, China.
Summary: Background: Highly pathogenic respiratory RNA viruses such as SARS-CoV-2 and its associated syndrome COVID-19 pose a tremendous threat to the global public health. Innate immune responses to SARS-CoV-2 depend mainly upon the NF-κB-mediated inflammation. Identifying unknown host factors driving the NF-κB activation and inflammation is crucial for the development of immune intervention strategies. Methods: Published single-cell RNA sequencing (scRNA-seq) data was used to analyze the differential transcriptome profiles of bronchoalveolar lavage (BAL) cells between healthy individuals (n = 27) and patients with severe COVID-19 (n = 21), as well as the differential transcriptome profiles of peripheral blood mononuclear cells (PBMCs) between healthy individuals (n = 22) and severely ill patients with COVID-19 (n = 45) or influenza (n = 16). Loss-of-function and gain-of-function assays were performed in diverse viruses-infected cells and male mice models to identify the role of TOMM34 in antiviral innate immunity. Findings: TOMM34, together with a list of genes encoding pro-inflammatory cytokines and antiviral immune proteins, was transcriptionally upregulated in circulating monocytes, lung epithelium and innate immune cells from individuals with severe COVID-19 or influenza. Deficiency of TOMM34/Tomm34 significantly impaired the type I interferon responses and NF-κB-mediated inflammation in various human/murine cell lines, murine bone marrow-derived macrophages (BMDMs) and in vivo. Mechanistically, TOMM34 recruits TRAF6 to facilitate the K63-linked polyubiquitination of NEMO upon viral infection, thus promoting the downstream NF-κB activation. Interpretation: In this study, viral induction of TOMM34 is positively correlated with the hyperinflammation in severely ill patients with COVID-19 and influenza. Our findings also highlight the physiological role of TOMM34 in the innate antiviral signallings. Funding: A full list of funding sources can be found in the acknowledgements section.
