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

Nat Commun. 2024 Oct 10;15(1):8794. doi: 10.1038/s41467-024-53149-w.

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.

MeSH terms

  • Animals
  • Bacterial Proteins* / genetics
  • Bacterial Proteins* / metabolism
  • Bacteroides / genetics
  • Bacteroides / metabolism
  • Bacteroides fragilis* / genetics
  • Bacteroides fragilis* / metabolism
  • Cryoelectron Microscopy
  • DNA Transposable Elements / genetics
  • Female
  • Gastrointestinal Microbiome
  • Humans
  • Membrane Transport Proteins* / genetics
  • Membrane Transport Proteins* / metabolism
  • Mice
  • Species Specificity
  • Ubiquitin / metabolism

Substances

  • Bacterial Proteins
  • Membrane Transport Proteins
  • Ubiquitin
  • DNA Transposable Elements