Structural disruption of Ntox15 nuclease effector domains by immunity proteins protects against type VI secretion system intoxication in Bacteroidales

Dustin E Bosch; Romina Abbasian; Bishal Parajuli; S Brook Peterson; Joseph D Mougous

doi:10.1128/mbio.01039-23

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Structural disruption of Ntox15 nuclease effector domains by immunity proteins protects against type VI secretion system intoxication in Bacteroidales

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Structural disruption of Ntox15 nuclease effector domains by immunity proteins protects against type VI secretion system intoxication in Bacteroidales

Dustin E Bosch, Romina Abbasian, Bishal Parajuli, S Brook Peterson and Joseph D Mougous

mBio, Vol.14(4), e0103923

08/31/2023

DOI: 10.1128/mbio.01039-23

PMCID: PMC10470768

PMID: 37345922

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Abstract

Bacteroidales use type VI secretion systems (T6SS) to competitively colonize and persist in the colon. We identify a horizontally transferred T6SS with Ntox15 family nuclease effector (Tde1) that mediates interbacterial antagonism among Bacteroidales, including several derived from a single human donor. Expression of cognate (Tdi1) or orphan immunity proteins in acquired interbacterial defense systems protects against Tde1-dependent attack. We find that immunity protein interaction induces a large effector conformational change in Tde nucleases, disrupting the active site and altering the DNA-binding site. Crystallographic snapshots of isolated Tde1, the Tde1/Tdi1 complex, and homologs from Phocaeicola vulgatus (Tde2/Tdi2) illustrate a conserved mechanism of immunity inserting into the central core of Tde, splitting the nuclease fold into two subdomains. The Tde/Tdi interface and immunity mechanism are distinct from all other polymorphic toxin–immunity interactions of known structure. Bacteroidales abundance has been linked to inflammatory bowel disease activity in prior studies, and we demonstrate that Tde and T6SS structural genes are each enriched in fecal metagenomes from ulcerative colitis subjects. Genetically mobile Tde1-encoding T6SS in Bacteroidales mediate competitive growth and may be involved in inflammatory bowel disease. Broad immunity is conferred by Tdi1 homologs through a fold-disrupting mechanism unique among polymorphic effector–immunity pairs of known structure.

Details

Title: Subtitle: Structural disruption of Ntox15 nuclease effector domains by immunity proteins protects against type VI secretion system intoxication in Bacteroidales
Creators: Dustin E Bosch
Romina Abbasian - University of Iowa
Bishal Parajuli - University of Iowa
S Brook Peterson - University of Washington
Joseph D Mougous - University of Washington
Resource Type: Journal article
Publication Details: mBio, Vol.14(4), e0103923
DOI: 10.1128/mbio.01039-23
PMID: 37345922
PMCID: PMC10470768
NLM abbreviation: mBio
eISSN: 2150-7511
Grant note: DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: K08 AI159619; DOI: 10.13039/100000060, name: HHS | NIH | National Institute of Allergy and Infectious Diseases, award: AI080609
Language: English
Electronic publication date: 06/22/2023
Date published: 08/31/2023
Academic Unit: Pathology
Record Identifier: 9984436460302771

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