A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy

Qiyao Chai, Xudong Wang, Lihua Qiang, Yong Zhang, Pupu Ge, Zhe Lu, Yanzhao Zhong, Bingxi Li, Jing Wang, Lingqiang Zhang, Dawang Zhou, Wei Li, Wenzhu Dong, Yu Pang, George Fu Gao and Cui Hua Liu ()
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Qiyao Chai: Chinese Academy of Sciences
Xudong Wang: Chinese Academy of Sciences
Lihua Qiang: Chinese Academy of Sciences
Yong Zhang: Chinese Academy of Sciences
Pupu Ge: Chinese Academy of Sciences
Zhe Lu: Chinese Academy of Sciences
Yanzhao Zhong: Chinese Academy of Sciences
Bingxi Li: Chinese Academy of Sciences
Jing Wang: Chinese Academy of Sciences
Lingqiang Zhang: Beijing Institute of Lifeomics
Dawang Zhou: Xiamen University
Wei Li: Chinese Academy of Sciences
Wenzhu Dong: Capital Medical University
Yu Pang: Capital Medical University
George Fu Gao: Chinese Academy of Sciences
Cui Hua Liu: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract Ubiquitin-mediated xenophagy, a type of selective autophagy, plays crucial roles in host defense against intracellular pathogens including Mycobacterium tuberculosis (Mtb). However, the exact mechanism by which host ubiquitin targets invaded microbes to trigger xenophagy remains obscure. Here we show that ubiquitin could recognize Mtb surface protein Rv1468c, a previously unidentified ubiquitin-binding protein containing a eukaryotic-like ubiquitin-associated (UBA) domain. The UBA-mediated direct binding of ubiquitin to, but not E3 ubiquitin ligases-mediated ubiquitination of, Rv1468c recruits autophagy receptor p62 to deliver mycobacteria into LC3-associated autophagosomes. Disruption of Rv1468c-ubiquitin interaction attenuates xenophagic clearance of Mtb in macrophages, and increases bacterial loads in mice with elevated inflammatory responses. Together, our findings reveal a unique mechanism of host xenophagy triggered by direct binding of ubiquitin to the pathogen surface protein, and indicate a diplomatic strategy adopted by Mtb to benefit its persistent intracellular infection through controlling intracellular bacterial loads and restricting host inflammatory responses.

Date: 2019
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DOI: 10.1038/s41467-019-09955-8

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