State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, China.
NHC Key Laboratory of Digestive Diseases, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai Cancer Institute, Shanghai, 200001, China.
Nat Commun. 2024 Oct 10;15(1):8794. doi: 10.1038/s41467-024-53149-w.
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.
各种细菌之间的有效竞争和多样化的防御策略在密集微生物群落中获得优势地位中起着至关重要的作用。肠道共生菌脆弱拟杆菌分泌一种抗菌泛素同源物（BfUbb），该物质靶向一种必需的周质 PPIase，以促进种内细菌竞争。然而，BfUbb 进入周质的机制及其潜在的种间拮抗作用仍知之甚少。在这里，我们通过转座子诱变鉴定出脆弱拟杆菌中一种高度保守的 TonB 依赖性转运体 SusCD（命名为 ButCD）是 BfUbb 的转运体。作为一种假定的蛋白相关营养物质利用系统，ButCD 在不同的拟杆菌物种中广泛分布，具有不同的序列相似性，导致不同的拟杆菌泛素同源物（BUbb）的导入效率不同，从而决定了 BUbb 的种间毒性特异性。BfUbb-ButCD 复合物的冷冻电镜结构和功能研究揭示了 ButC 的独特结构特征，这些特征对于其被 BfUbb 靶向至关重要。动物研究进一步证明了 BfUbb 能够特异性和有效地消除肠道中的肠毒素脆弱拟杆菌（ETBF），提示其具有作为治疗 ETBF 相关炎症性肠病和结直肠癌的潜力。我们的研究结果全面阐明了 BUbb 表现出的种间毒性，并探索了其潜在的应用。
