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Cell Syst. 2018 Sep 26;7(3):323-338.e6. doi: 10.1016/j.cels.2018.06.010. Epub 2018 Aug 1.

Quantitative Yeast Genetic Interaction Profiling of Bacterial Effector Proteins Uncovers a Role for the Human Retromer in Salmonella Infection.

Author information

1
Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77802, USA.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, CA 94158, USA; J. David Gladstone Institute, San Francisco, CA 94158, USA.
3
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
4
Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77802, USA; Department of Veterinary Pathobiology, Texas A&M College of Veterinary Medicine and Biomedical Sciences, College Station, TX 77843, USA; Norman Borlaug Center, Texas A&M University, College Station, TX 77843, USA.
5
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, CA 94158, USA.
6
Department of Veterinary Pathobiology, Texas A&M College of Veterinary Medicine and Biomedical Sciences, College Station, TX 77843, USA.
7
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, CA 94158, USA; J. David Gladstone Institute, San Francisco, CA 94158, USA. Electronic address: nevan.krogan@ucsf.edu.
8
Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, Bryan, TX 77802, USA. Electronic address: robert.watson@medicine.tamhsc.edu.

Abstract

Intracellular bacterial pathogens secrete a repertoire of effector proteins into host cells that are required to hijack cellular pathways and cause disease. Despite decades of research, the molecular functions of most bacterial effectors remain unclear. To address this gap, we generated quantitative genetic interaction profiles between 36 validated and putative effectors from three evolutionarily divergent human bacterial pathogens and 4,190 yeast deletion strains. Correlating effector-generated profiles with those of yeast mutants, we recapitulated known biology for several effectors with remarkable specificity and predicted previously unknown functions for others. Biochemical and functional validation in human cells revealed a role for an uncharacterized component of the Salmonella SPI-2 translocon, SseC, in regulating maintenance of the Salmonella vacuole through interactions with components of the host retromer complex. These results exhibit the power of genetic interaction profiling to discover and dissect complex biology at the host-pathogen interface.

KEYWORDS:

E-MAP; Salmonella enterica serovar Typhimurium; bacterial effector protein; genetic interaction profile; host-pathogen interaction; intracellular bacteria; retromer complex

PMID:
30077634
PMCID:
PMC6160342
[Available on 2019-09-26]
DOI:
10.1016/j.cels.2018.06.010
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