Functional diversification of the NleG effector family in enterohemorrhagic Escherichia coli

Dylan Valleau, Dustin J. Little, Dominika Borek, Tatiana Skarina, Andrew T. Quaile, Rosa Di Leo, Scott Houliston, Alexander Lemak, Cheryl H. Arrowsmith, Brian K. Coombes, Alexei Savchenko

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

The pathogenic strategy of Escherichia coli and many other gramnegative pathogens relies on the translocation of a specific set of proteins, called effectors, into the eukaryotic host cell during infection. These effectors act in concert to modulate host cell processes in favor of the invading pathogen. Injected by the type III secretion system (T3SS), the effector arsenal of enterohemorrhagic E. coli (EHEC) O157:H7 features at least eight individual NleG effectors, which are also found across diverse attaching and effacing pathogens. NleG effectors share a conserved C-terminal U-box E3 ubiquitin ligase domain that engages with host ubiquitination machinery. However, their specific functions and ubiquitination targets have remained uncharacterized. Here, we identify host proteins targeted for ubiquitination-mediated degradation by two EHEC NleG family members, NleG5-1 and NleG2-3. NleG5-1 localizes to the host cell nucleus and targets the MED15 subunit of the Mediator complex, while NleG2-3 resides in the host cytosol and triggers degradation of Hexokinase-2 and SNAP29. Our structural studies of NleG5-1 reveal a distinct N-terminal α/β domain that is responsible for interacting with host protein targets. The core of this domain is conserved across the NleG family, suggesting this domain is present in functionally distinct NleG effectors, which evolved diversified surface residues to interact with specific host proteins. This is a demonstration of the functional diversification and the range of host proteins targeted by the most expanded effector family in the pathogenic arsenal of E. coli.

Original languageEnglish (US)
Pages (from-to)10004-10009
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number40
DOIs
StatePublished - Oct 2 2018

Keywords

  • Effectors
  • Escherichia coli
  • Pathogenesis
  • Ubiquitination

ASJC Scopus subject areas

  • General

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    Valleau, D., Little, D. J., Borek, D., Skarina, T., Quaile, A. T., Leo, R. D., Houliston, S., Lemak, A., Arrowsmith, C. H., Coombes, B. K., & Savchenko, A. (2018). Functional diversification of the NleG effector family in enterohemorrhagic Escherichia coli. Proceedings of the National Academy of Sciences of the United States of America, 115(40), 10004-10009. https://doi.org/10.1073/pnas.1718350115