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Cited by 5Ubiquitin and proteasome pathwaysBacterial Genetics and BiotechnologyBacteriophages and microbial interactions

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Mechanistic basis for protein conjugation in a diverged bacterial ubiquitination pathway

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Ye, Qiaozhen, Gong, Minheng, Cai, Jiaxi, Chambers, Lydia R., Zhou, Huilin, Suhandynata, Raymond T., Corbett, Kevin D.·2026·Nature Structural & Molecular Biology
DOI 10.1038/s41594-025-01696-1PMC PMC12885553

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Abstract

Ubiquitination is a fundamental eukaryotic protein post-translational modification pathway, in which ubiquitin or a ubiquitin-like protein (Ubl) is typically conjugated to a lysine of a target protein. Ubiquitination is initiated by adenylation of the Ubl C terminus, followed by sequential formation of Ubl-cysteine thioester intermediates with E1, E2 and (optionally) E3 proteins before formation of the final Ubl-lysine isopeptide linkage. Recent work has revealed two ubiquitination-related bacterial pathways in the context of antiphage immunity. Bioinformatics analyses have hinted at the existence of additional uncharacterized bacterial pathways that include ubiquitination-like machinery. Here, we describe the architecture and biochemical mechanisms of an alternative Bub (bacterial ubiquitination-like) pathway, revealing structural parallels and mechanistic differences when compared to other ubiquitination pathways. We show that Bub operons encode functional E1, E2 and Ubl proteins that are related to their eukaryotic counterparts but likely function through oxyester rather than thioester intermediates. We also identify an enzyme family in Bub operons with a conserved catalytic site and a role in Ubl-target conjugation. The genomic context of Bub operons suggests that they also function in antiphage immunity and we present evidence that one Bub pathway may regulate translation in response to stress. Overall, our results reveal an uncharacterized family of bacterial ubiquitination-related pathways with a distinctive biochemical mechanism.

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Metadata

Authors
Ye, Q., Gong, M., Cai, J., Chambers, L. R., Zhou, H., Suhandynata, R. T., & Corbett, K. D.
Affiliations
  • University of California San Diego (US)
  • Harvard University (US)
Corresponding author
Corbett, Kevin D.
ORCID
Venue
Nature Structural & Molecular Biology
Publisher
Springer Science and Business Media LLC
Published
2025-11-03
Volume
33
Issue
1
Pages
71-83
ISSN
  • 1545-9985 (ISSN-L)
  • 1545-9993
DOI
10.1038/s41594-025-01696-1
PMC
PMC12885553
OpenAlex
W4415790288
Cited by
5
References
5
Citations by year
2026: 2 · 2025: 2
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Structural & Molecular Biology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • U.S. Department of Energy (76SF00515, DE–AC02–76SF00515, P41GM103393, AC02‐76SF00515, DE-AC02-)
  • National Institutes of Health (DE-AC02-76SF00515, 1r35gm156288-01)
  • Office of Science (AC02-76SF00515, P41GM103393, DE-AC02-76SF0051 5, DE-AC02, 76SF00515)
  • University of California, San Diego
  • National Institute of General Medical Sciences (DE-AC02-76SF00515, GM144121, P41GM103393, R35GM144121, R01GM151191, T32GM139795)
  • National Institute of Allergy and Infectious Diseases (F31AI194603)
  • Basic Energy Sciences (DE-AC02, P41GM103393, 76SF00515, AC02-76SF00515, DE-AC-02-76SF00515)
  • Biological and Environmental Research (P41 GM103393, DE- AC0276SF00515)
  • SLAC National Accelerator Laboratory (DEAC02−76SF00515, AC02‐76SF00515, P41GM103393)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Immunology and Microbiology › Virology › Bacteriophages and microbial interactions
Keywords
ubiquitin-like proteins, protein conjugation, translational regulation, stress response, post-translational modification

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