Bacterial effector restricts liquid-liquid phase separation of ZPR1 to antagonize host UPRER
Xiaoxiao Ouyang,
Xueyun Wang,
Pan Li,
Qin Huang,
Li Zhou,
Jingxiang Li,
Li Gao,
Qi Sun,
Fangni Chai,
Shupan Guo,
Zhihui Zhou,
Xin Liu,
Lunzhi Dai,
Wei Cheng,
Haiyan Ren
Affiliations
Xiaoxiao Ouyang
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Xueyun Wang
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Pan Li
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Qin Huang
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Li Zhou
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Jingxiang Li
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Li Gao
Department of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, and Sichuan University, Chengdu 610041, China
Qi Sun
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Fangni Chai
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Shupan Guo
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Zhihui Zhou
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Xin Liu
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
Lunzhi Dai
Department of General Practice and National Clinical Research Center for Geriatrics, State Key Laboratory of Biotherapy, West China Hospital, and Sichuan University, Chengdu 610041, China
Wei Cheng
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Collaborative Innovation Center of Biotherapy, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China
Haiyan Ren
Department of Pulmonary and Critical Care, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Collaborative Innovation Center of Biotherapy, Sichuan University West China Hospital, Chengdu, Sichuan 610041, China; Corresponding author
Summary: How pathogens manipulate host UPRER to mediate immune evasion is largely unknown. Here, we identify the host zinc finger protein ZPR1 as an interacting partner of the enteropathogenic E. coli (EPEC) effector NleE using proximity-enabled protein crosslinking. We show that ZPR1 assembles via liquid-liquid phase separation (LLPS) in vitro and regulates CHOP-mediated UPRER at the transcriptional level. Interestingly, in vitro studies show that the ZPR1 binding ability with K63-ubiquitin chains, which promotes LLPS of ZPR1, is disrupted by NleE. Further analyses indicate that EPEC restricts host UPRER pathways at the transcription level in a NleE-ZPR1 cascade-dependent manner. Together, our study reveals the mechanism by which EPEC interferes with CHOP-UPRER via regulating ZPR1 to help pathogens escape host defense.
