Genetically incorporated crosslinkers reveal NleE attenuates host autophagy dependent on PSMD10

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Abstract

Autophagy acts as a pivotal innate immune response against infection. Some virulence effectors subvert the host autophagic machinery to escape the surveillance of autophagy. The mechanism by which pathogens interact with host autophagy remains mostly unclear. However, traditional strategies often have difficulty identifying host proteins that interact with effectors due to the weak, dynamic and transient nature of these interactions. Here, we found that Enteropathogenic Escherichia coli (EPEC) regulates autophagosome formation in host cells dependent on effector NleE. The 26S Proteasome Regulatory Subunit 10 (PSMD10) was identified as a direct interaction partner of NleE in living cells by employing genetically incorporated crosslinkers. Pairwise chemical crosslinking revealed that NleE interacts with the N-terminus of PSMD10. We demonstrated that PSMD10 homodimerization is necessary for its interaction with ATG7 and promotion of autophagy, but not necessary for PSMD10 interaction with ATG12. Therefore, NleE-mediated PSMD10 in monomeric state attenuates host autophagosome formation. Our study reveals the mechanism through which EPEC attenuates host autophagy activity.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Jingxiang Li

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Shupan Guo

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Li Zhou

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Fangni Chai

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Qi Sun

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Pan Li

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Li Gao

West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Lunzhi Dai

West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Xiaoxiao Ouyang

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Zhihui Zhou

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Wei Cheng

West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Shiqian Qi

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Kefeng Lu

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

Competing interests
The authors declare that no competing interests exist.
Haiyan Ren

Division of Respiratory and Critical Care Medicine, State Key Laboratory of Biotherapy, West China Hospital of Sichuan University and Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China

For correspondence
hyren@scu.edu.cn

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9995-3255

Funding

National Key Research and Development Program of China (2018YFC1002802)

Haiyan Ren

National Key Research and Development Program of China (2018YFA0109200)

Haiyan Ren

National Natural Science Foundation of China (31872727)

Haiyan Ren

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.