A highly conserved SusCD transporter determines the import and species-specific antagonism of Bacteroides ubiquitin homologues

Ming Tong, Jinghua Xu, Weixun Li, Kun Jiang, Yan Yang, Zhe Chen, Xuyao Jiao, Xiangfeng Meng, Mingyu Wang, Jie Hong, Hongan Long, Shuang-Jiang Liu, Bentley Lim and Xiang Gao ()
Additional contact information
Ming Tong: Shandong University
Jinghua Xu: Shandong University
Weixun Li: Shandong University
Kun Jiang: Shandong University
Yan Yang: Shandong University
Zhe Chen: Shandong University
Xuyao Jiao: Shandong University
Xiangfeng Meng: Shandong University
Mingyu Wang: Shandong University
Jie Hong: Shanghai Cancer Institute
Hongan Long: Ocean University of China
Shuang-Jiang Liu: Shandong University
Bentley Lim: Yale University School of Medicine
Xiang Gao: Shandong University

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Efficient interbacterial competitions and diverse defensive strategies employed by various bacteria play a crucial role in acquiring a hold within a dense microbial community. The gut symbiont Bacteroides fragilis secretes an antimicrobial ubiquitin homologue (BfUbb) that targets an essential periplasmic PPIase to drive intraspecies bacterial competition. However, the mechanisms by which BfUbb enters the periplasm and its potential for interspecies antagonism remain poorly understood. Here, we employ transposon mutagenesis and identify a highly conserved TonB-dependent transporter SusCD (designated as ButCD) in B. fragilis as the BfUbb transporter. As a putative protein-related nutrient utilization system, ButCD is widely distributed across diverse Bacteroides species with varying sequence similarity, resulting in distinct import efficiency of Bacteroides ubiquitin homologues (BUbb) and thereby determining the species-specific toxicity of BUbb. Cryo-EM structural and functional investigations of the BfUbb–ButCD complex uncover distinctive structural features of ButC that are crucial for its targeting by BfUbb. Animal studies further demonstrate the specific and efficient elimination of enterotoxigenic B. fragilis (ETBF) in the murine gut by BfUbb, suggesting its potential as a therapeutic against ETBF-associated inflammatory bowel disease and colorectal cancer. Our findings provide a comprehensive elucidation of the species-specific toxicity exhibited by BUbb and explore its potential applications.

Date: 2024
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DOI: 10.1038/s41467-024-53149-w

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