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Proc Natl Acad Sci U S A. 2018 Oct 2;115(40):10004-10009. doi: 10.1073/pnas.1718350115. Epub 2018 Sep 14.

Functional diversification of the NleG effector family in enterohemorrhagic Escherichia coli.

Author information

1
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada.
2
Department of Biochemistry and Biomedical Sciences, Michael G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON L8S 4K1, Canada.
3
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Princess Margaret Cancer Centre, University of Toronto, Toronto, ON M5G 2M9, Canada.
6
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
7
Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON M5S 3E5, Canada; alexei.savchenko@ucalgary.ca.
8
Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB T2N 4N1, Canada.

Abstract

The pathogenic strategy of Escherichia coli and many other gram-negative 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.

KEYWORDS:

Escherichia coli; effectors; pathogenesis; ubiquitination

PMID:
30217892
PMCID:
PMC6176568
[Available on 2019-04-02]
DOI:
10.1073/pnas.1718350115
[Indexed for MEDLINE]

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