MARTX toxins as effector delivery platforms

Gavin, Hannah E.; Satchell, K.J.F.

doi:10.1093/femspd/ftv092

Cited by 37 publications

(37 citation statements)

References 73 publications

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“…The pore is thought to serve as the route for translocation of the central toxin region containing the CPD and effector domains across the eukaryotic plasma membrane from the extracellular space to the cytosol of target cells. Stimulated by the eukaryotic-specific molecule inositol hexakisphosphate, the CPD is activated to cleave after leucine residues located between effector domains, thereby releasing bacterial effector proteins into the cytosol of the targeted eukaryotic cell [20]. …”

Section: Introductionmentioning

confidence: 99%

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

2017

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Vibrio vulnificus causes highly lethal bacterial infections in which the Multifunctional Autoprocessing Repeats-in-Toxins (MARTX) toxin product of the rtxA1 gene is a key virulence factor. MARTX toxins are secreted proteins up to 5208 amino acids in size. Conserved MARTX N- and C-terminal repeat regions work in concert to form pores in eukaryotic cell membranes, through which the toxin’s central region of modular effector domains is translocated. Upon inositol hexakisphosphate-induced activation of the of the MARTX cysteine protease domain (CPD) in the eukaryotic cytosol, effector domains are released from the holotoxin by autoproteolytic activity. We previously reported that the native MARTX toxin effector domain repertoire is dispensable for epithelial cellular necrosis in vitro, but essential for cell rounding and apoptosis prior to necrotic cell death. Here we use an intragastric mouse model to demonstrate that the effector domain region is required for bacterial virulence during intragastric infection. The MARTX effector domain region is essential for bacterial dissemination from the intestine, but dissemination occurs in the absence of overt intestinal tissue pathology. We employ an in vitro model of V. vulnificus interaction with polarized colonic epithelial cells to show that the MARTX effector domain region induces rapid intestinal barrier dysfunction and increased paracellular permeability prior to onset of cell lysis. Together, these results negate the inherent assumption that observations of necrosis in vitro directly predict bacterial virulence, and indicate a paradigm shift in our conceptual understanding of MARTX toxin function during intestinal infection. Results implicate the MARTX effector domain region in mediating early bacterial dissemination from the intestine to distal organs–a key step in V. vulnificus foodborne pathogenesis–even before onset of overt intestinal pathology.

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Section: Introductionmentioning

confidence: 99%

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

2017

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“…Expression of the MARTX toxin can increase lethality of V. vulnificus up to 2,600-fold (Kwak, Jeong, & Satchell, 2011). The MARTX toxin thus serves as an effector delivery platform for translocation of multiple toxic virulence factors inside cells as a single bolus (Gavin & Satchell, 2015;Kim, 2018;Satchell, 2015). It is composed of conserved glycine-rich repeats at both the N-and C-termini between which there are variable effector domains and a cysteine protease domain (CPD).…”

mentioning

confidence: 99%

N‐terminal autoprocessing and acetylation of multifunctional‐autoprocessing repeats‐in‐toxins (MARTX) Makes Caterpillars Floppy‐like effector is stimulated by adenosine diphosphate (ADP)‐Ribosylation Factor 1 in advance of Golgi fragmentation

Herrera

Muroski

Sengupta

et al. 2019

Cellular Microbiology

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Studies have successfully elucidated the mechanism of action of several effector domains that comprise the multifunctional-autoprocessing repeats-in-toxins (MARTX) toxins of Vibrio vulnificus. However, the biochemical linkage between the cysteine proteolytic activity of Makes Caterpillars Floppy (MCF)-like effector and its cellular effects remains unknown. In this study, we identify the host cell factors that activate in vivo and in vitro MCF autoprocessing as adenosine diphosphate (ADP)-Ribosylation Factor 1 (ARF1) and ADP-Ribosylation Factor 3 (ARF3).Autoprocessing activity is enhanced when ARF1 is in its active [guanosine triphosphate (GTP)-bound] form compared to the inactive [guanosine diphosphate (GDP)bound] form. Subsequent to auto-cleavage, MCF is acetylated on its exposed N-terminal glycine residue. Acetylation apparently does not dictate subcellular localization as MCF is found localized throughout the cell. However, the cleaved form of MCF gains the ability to bind to the specialized lipid phosphatidylinositol 5-phosphate enriched in Golgi and other membranes necessary for endocytic trafficking, suggesting that a fraction of MCF may be subcellularly localized. Traditional thin-section electron microscopy, high-resolution cryoAPEX localization, and fluorescent microscopy show that MCF causes Golgi dispersal resulting in extensive vesiculation. In addition, host mitochondria are disrupted and fragmented. Mass spectrometry analysis found no reproducible modifications of ARF1 suggesting that ARF1 is not posttranslationally modified by MCF. Further, catalytically active MCF does not stably associate with ARF1. Our data indicate not only that ARF1 is a cross-kingdom activator of MCF, but also that MCF may mediate cytotoxicity by directly targeting another yet to be identified protein. This study begins to elucidate the biochemical activity of this important domain and gives insight into how it may promote disease progression.

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“…Another PLA 1 which adopts the ␣/␤ hydrolase fold is found in a heterogeneous family of large toxins designated multifunctional autoprocessing repeats-in-toxin (MARTX) toxins, which are secreted through a type I secretion system by several Vibrio species and other Gram-negative bacteria of the genera Aeromonas, Proteus, Photorhabdus, and Xenorhabdus (127). MARTX toxins are composed of conserved repeat regions and an autoprocessing protease domain that functions as a delivery platform to transfer up to five cytopathic effectors in eukaryotic cells (128).…”

Section: Acyl Hydrolases: Phospholipases a And Bmentioning

confidence: 99%

“…This toxin, which promotes colonization of the small intestine in mice, includes as one of its effectors a PI 3-phosphate (PIP 3 )-specific PLA 1 that reduces the intracellular PIP 3 levels on endosomes and preautophagosomal structures, thus blocking endosomal and autophagic pathways, preventing bacterial clearance, and facilitating bacterial survival (129). The MARTX toxin of the opportunistic pathogen Vibrio vulnificus, which plays a role in defense against predation by amoeba and is required for full virulence in mammals, also encompasses a domain predicted to adopt the ␣/␤ hydrolase fold (127), although its exact role in pathogenicity has not been clarified.…”

Section: Acyl Hydrolases: Phospholipases a And Bmentioning

confidence: 99%

Bacterial Sphingomyelinases and Phospholipases as Virulence Factors

Flores-Dı́az

Monturiol-Gross

Naylor

et al. 2016

Microbiol Mol Biol Rev

165

143

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SUMMARYBacterial sphingomyelinases and phospholipases are a heterogeneous group of esterases which are usually surface associated or secreted by a wide variety of Gram-positive and Gram-negative bacteria. These enzymes hydrolyze sphingomyelin and glycerophospholipids, respectively, generating products identical to the ones produced by eukaryotic enzymes which play crucial roles in distinct physiological processes, including membrane dynamics, cellular signaling, migration, growth, and death. Several bacterial sphingomyelinases and phospholipases are essential for virulence of extracellular, facultative, or obligate intracellular pathogens, as these enzymes contribute to phagosomal escape or phagosomal maturation avoidance, favoring tissue colonization, infection establishment and progression, or immune response evasion. This work presents a classification proposal for bacterial sphingomyelinases and phospholipases that considers not only their enzymatic activities but also their structural aspects. An overview of the main physiopathological activities is provided for each enzyme type, as are examples in which inactivation of a sphingomyelinase- or a phospholipase-encoding gene impairs the virulence of a pathogen. The identification of sphingomyelinases and phospholipases important for bacterial pathogenesis and the development of inhibitors for these enzymes could generate candidate vaccines and therapeutic agents, which will diminish the impacts of the associated human and animal diseases.

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MARTX toxins as effector delivery platforms

Cited by 37 publications

References 73 publications

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

The Effector Domain Region of the Vibrio vulnificus MARTX Toxin Confers Biphasic Epithelial Barrier Disruption and Is Essential for Systemic Spread from the Intestine

N‐terminal autoprocessing and acetylation of multifunctional‐autoprocessing repeats‐in‐toxins (MARTX) Makes Caterpillars Floppy‐like effector is stimulated by adenosine diphosphate (ADP)‐Ribosylation Factor 1 in advance of Golgi fragmentation

Bacterial Sphingomyelinases and Phospholipases as Virulence Factors

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