The vacuole guard hypothesis: how intravacuolar pathogens fight to maintain the integrity of their beloved home

Anand, Ila S.; Choi, Wonyoung; Isberg, Ralph R.

doi:10.1016/j.mib.2020.01.008

Cited by 18 publications

(9 citation statements)

References 53 publications

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“…Loss of vacuolar integrity due to the activity of microbial secretion systems constitutes a ‘pattern of pathogenesis’ recognized by GBPs and other immune sensors. Accordingly, many vacuolar pathogens evolved mechanisms to minimize or repair vacuolar damage [106]. The existence of a second detection system enables the host cell to direct GBPs to PCVs lacking obvious hallmarks of vacuolar damage.…”

Section: Gbps Are Regulators Of Inflammation and Antimicrobial Host Defensementioning

confidence: 99%

Human guanylate binding proteins: nanomachines orchestrating host defense

Kutsch

Coers

2021

The FEBS Journal

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The ability of any single cell of our body to defend itself against intracellular pathogens is a critical aspect of the human immune system. Many of our cells’ intrinsic defenses are orchestrated by a set of guanylate binding proteins (GBPs). Here, we synthesize recent studies to generate a comprehensive model for the biochemical and cell biological mechanisms by which GBPs defend against protozoan, bacterial, and viral pathogens.

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Section: Gbps Are Regulators Of Inflammation and Antimicrobial Host Defensementioning

confidence: 99%

Human guanylate binding proteins: nanomachines orchestrating host defense

Kutsch

Coers

2021

The FEBS Journal

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“…As we have previously argued, SdhA belongs to a larger class of pathogen proteins called vacuole guards that act to prevent intravacuolar microbial pathogens from being attacked by disruptive membrane components largely derived from endosomes and recycling compartments ( Anand et al, 2020b ). Although it may be predicted that such interactions would lead to trafficking of the LCV to the lysosome, interaction of endocytic compartments with pathogen-containing vacuoles has consistently resulted in disruption of the vacuole ( Anand et al, 2020a ; Mellouk et al, 2014 ). This is likely because pathogen proteins inserted into the vacuole result in specific phospholipid requirements for maintaining vacuole homeostasis, with docking of endocytic vesicles disrupting this homeostasis.…”

Section: Discussionmentioning

confidence: 99%

SdhA blocks disruption of the Legionella-containing vacuole by hijacking the OCRL phosphatase

et al. 2021

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SUMMARY Legionella pneumophila grows intracellularly within a replication vacuole via action of Icm/Dot-secreted proteins. One such protein, SdhA, maintains the integrity of the vacuolar membrane, thereby preventing cytoplasmic degradation of bacteria. We show here that SdhA binds and blocks the action of OCRL (OculoCerebroRenal syndrome of Lowe), an inositol 5-phosphatase pivotal for controlling endosomal dynamics. OCRL depletion results in enhanced vacuole integrity and intracellular growth of a sdhA mutant, consistent with OCRL participating in vacuole disruption. Overexpressed SdhA alters OCRL function, enlarging endosomes, driving endosomal accumulation of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P 2 ), and interfering with endosomal trafficking. SdhA interrupts Rab guanosine triphosphatase (GTPase)-OCRL interactions by binding to the OCRL ASPM-SPD2-Hydin (ASH) domain, without directly altering OCRL 5-phosphatase activity. The Legionella vacuole encompassing the sdhA mutant accumulates OCRL and endosomal antigen EEA1 (Early Endosome Antigen 1), consistent with SdhA blocking accumulation of OCRL-containing endosomal vesicles. Therefore, SdhA hijacking of OCRL is associated with blocking trafficking events that disrupt the pathogen vacuole.

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“…The membrane trafficking hypothesis. Membrane trafficking, which is becoming increasingly recognized as being regulated by Rho GTPases [36,37] is emerging as a key influencer of pathogen vacuolar stability in the field of host-pathogen interactions [38]. There are…”

Section: How Does Rhoa Restrict Dmv Escape?mentioning

confidence: 99%

The type three secretion system effector protein IpgB1 promotes Shigella flexneri cell-to-cell spread through double-membrane vacuole escape

et al. 2022

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S. flexneri is an important human pathogen that causes bacillary dysentery. During infection, S. flexneri invades colonic epithelial cells, hijacks the host cell cytoskeleton to move in the cytosol of infected cells, and spreads from cell to cell through formation of membrane protrusions that project into adjacent cells and resolve into double membrane vacuoles (DMVs). S. flexneri cell-to-cell spread requires the integrity of the bacterial type three secretion system (T3SS). However, the exact role of the T3SS effector proteins in the dissemination process remains poorly understood. Here, we investigated the role of the T3SS effector protein IpgB1 in S. flexneri dissemination. IpgB1 was previously characterized as a guanine nucleotide exchange factor (GEF) that contributes to invasion. In addition to the invasion defect, we showed that the ipgB1 mutant formed smaller infection foci in HT-29 cells. Complementation of this phenotype required the GEF activity of IpgB1. Using live confocal microscopy, we showed that the ipgB1 mutant is specifically impaired in DMV escape. Depletion of Rac1, the host cell target of IpgB1 during invasion, as well as pharmacological inhibition of Rac1 signaling, reduced cell-to-cell spread and DMV escape. In a targeted siRNA screen, we uncovered that RhoA depletion restored ipgB1 cell-to-cell spread and DMV escape, revealing a critical role for the IpgB1-Rac1 axis in antagonizing RhoA-mediated restriction of DMV escape. Using an infant rabbit model of shigellosis, we showed that the ipgB1 mutant formed fewer and smaller infection foci in colons of infected animals, which correlated with attenuated symptoms of disease, including epithelial fenestration and bloody diarrhea. Our results demonstrate that, in addition to its role during invasion, IpgB1 modulates Rho family small GTPase signaling to promote cell-to-cell spread, DMV escape, and S. flexneri pathogenesis.

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The vacuole guard hypothesis: how intravacuolar pathogens fight to maintain the integrity of their beloved home

Cited by 18 publications

References 53 publications

Human guanylate binding proteins: nanomachines orchestrating host defense

Human guanylate binding proteins: nanomachines orchestrating host defense

SdhA blocks disruption of the Legionella-containing vacuole by hijacking the OCRL phosphatase

The type three secretion system effector protein IpgB1 promotes Shigella flexneri cell-to-cell spread through double-membrane vacuole escape

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