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Formylglycine-generating enzyme-like proteins constitute a novel family of widespread type VI secretion system immunity proteins

Juvenal Lopez, Nguyen-Hung Le, View ORCID ProfileKi Hwan Moon, Dor Salomon, Eran Bosis, Mario F. Feldman
doi: https://doi.org/10.1101/2021.05.21.445229
Juvenal Lopez
1Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
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Nguyen-Hung Le
1Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
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Ki Hwan Moon
1Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
2Division of Convergence on Marine Science, Korea Maritime and Ocean University, Busan, Korea 49112
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  • ORCID record for Ki Hwan Moon
Dor Salomon
3Department of Clinical Microbiology and Immunology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
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Eran Bosis
4Department of Biotechnology Engineering, ORT Braude College of Engineering, Karmiel, Israel
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  • For correspondence: bosis@braude.ac.il mariofeldman@wustl.edu
Mario F. Feldman
1Department of Molecular Microbiology, Washington University in St. Louis, School of Medicine, St. Louis, MO, USA
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  • For correspondence: bosis@braude.ac.il mariofeldman@wustl.edu
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Abstract

Competition is a critical aspect of bacterial life, as it enables niche establishment and facilitates the acquisition of essential nutrients. Warfare between Gram-negative bacteria is largely mediated by the type VI secretion system (T6SS), a dynamic nanoweapon that delivers toxic effector proteins from an attacking cell to adjacent bacteria in a contact-dependent manner. Effector-encoding bacteria prevent self-intoxication and kin cell killing by the expression of immunity proteins, which prevent effector toxicity by specifically binding their cognate effector and occluding its active site. In this study, we investigate Tsi3, a previously uncharacterized T6SS immunity protein present in multiple strains of the human pathogen Acinetobacter baumannii. We show that Tsi3 is the cognate immunity protein of the antibacterial effector of unknown function Tse3. Our bioinformatic analyses indicate that Tsi3 homologs are widespread among Gram-negative bacteria, often encoded within T6SS effector-immunity modules. Surprisingly, we found that Tsi3 homologs possess a characteristic formylglycine-generating enzyme (FGE) domain, which is present in various enzymatic proteins. Our data shows that Tsi3-mediated immunity is dependent on Tse3-Tsi3 protein-protein interactions and that Tsi3 homologs from various bacteria do not protect against Tse3-dependent bacterial killing. Thus, we conclude that Tsi3 homologs are unlikely to be functional enzymes. Collectively, our work identifies FGE domain-containing proteins as important mediators of immunity against T6SS attacks and indicates that the FGE domain can be co-opted as a scaffold in multiple proteins to carry out diverse functions.

Importance Despite the wealth of knowledge on the diversity of biochemical activities carried out by T6SS effectors, comparably little is known about the various strategies bacteria employ to prevent susceptibility to T6SS-dependent bacterial killing. Our work establishes a novel family of T6SS immunity proteins with a characteristic FGE domain. This domain is present in enzymatic proteins with various catalytic activities. Our characterization of Tsi3 expands the known functions carried out by FGE-like proteins to include defense during T6SS-mediated bacterial warfare. Moreover, it highlights the evolution of FGE domain-containing proteins to carry out diverse biological functions.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 22, 2021.
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Formylglycine-generating enzyme-like proteins constitute a novel family of widespread type VI secretion system immunity proteins
Juvenal Lopez, Nguyen-Hung Le, Ki Hwan Moon, Dor Salomon, Eran Bosis, Mario F. Feldman
bioRxiv 2021.05.21.445229; doi: https://doi.org/10.1101/2021.05.21.445229
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Formylglycine-generating enzyme-like proteins constitute a novel family of widespread type VI secretion system immunity proteins
Juvenal Lopez, Nguyen-Hung Le, Ki Hwan Moon, Dor Salomon, Eran Bosis, Mario F. Feldman
bioRxiv 2021.05.21.445229; doi: https://doi.org/10.1101/2021.05.21.445229

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