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            <i>Vibrio</i>
            Effector Protein Is an Inositol Phosphatase and Disrupts Host Cell Membrane Integrity

Broberg, Christopher A.; Zhang, Lingling; Gonzalez, Herman; Laskowski-Arce, Michelle A.; Orth, Kim

doi:10.1126/science.1192850

Cited by 96 publications

(83 citation statements)

References 20 publications

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“…Because inositol phosphates are rarely found in bacteria (27), we postulate that the PH domain of VasX has a role in binding to host membrane lipids. Interference with host cell phosphoinositide metabolism and signaling by pathogenic bacteria is not uncommon and has been previously demonstrated for other enteric bacterial pathogens (8,16,31). VasX is not required for the export of the T6SS apparatus component Hcp (Fig.…”

Section: Discussionmentioning

confidence: 99%

Vibrio cholerae Requires the Type VI Secretion System Virulence Factor VasX To Kill Dictyostelium discoideum

et al. 2011

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The type VI secretion system (T6SS) is recognized as an important virulence mechanism in several Gram-negative pathogens. In Vibrio cholerae, the causative agent of the diarrheal disease cholera, a minimum of three gene clusters-one main cluster and two auxiliary clusters-are required to form a functional T6SS apparatus capable of conferring virulence toward eukaryotic and prokaryotic hosts. Despite an increasing understanding of the components that make up the T6SS apparatus, little is known about the regulation of these genes and the gene products delivered by this nanomachine. VasH is an important regulator of the V. cholerae T6SS. Here, we present evidence that VasH regulates the production of a newly identified protein, VasX, which in turn requires a functional T6SS for secretion. Deletion of vasX does not affect export or enzymatic function of the structural T6SS proteins Hcp and VgrG-1, suggesting that VasX is dispensable for the assembly of the physical translocon complex. VasX localizes to the bacterial membrane and interacts with membrane lipids. We present VasX as a novel virulence factor of the T6SS, as a V. cholerae mutant lacking vasX exhibits a phenotype of attenuated virulence toward Dictyostelium discoideum.Vibrio cholerae is the marine bacterium responsible for the diarrheal disease cholera. Multiple cholera pandemics have been caused by the O1 serogroup of V. cholerae, and recently, O139 has emerged as a new pandemic strain (11). The principal virulence factors postulated to be essential for the pandemic spread of strains belonging to these serogroups are cholera toxin (CT) and the toxin-coregulated pilus (TCP) (13, 17). Non-O1 and non-O139 serogroups of V. cholerae are also capable of causing disease, in some cases in the absence of CT and TCP (10). In 1968, the O37 serogroup strain V52 was responsible for an outbreak of cholera-like diarrheal illness in Sudan, with 460 cases leading to 125 deaths (42). The genome of V52 carries both CT and TCP genes, but whether this strain produces CT and TCP in vivo has not yet been determined. V52 possesses a constitutively active type VI secretion system (T6SS) that confers virulence toward phagocytic cells, including the social amoeba Dictyostelium discoideum and murine macrophages (34). Pandemic strains of V. cholerae also possess the full complement of T6SS genes, but it is currently unclear how the T6SS is activated and how this system contributes to human disease.

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Section: Discussionmentioning

confidence: 99%

Vibrio cholerae Requires the Type VI Secretion System Virulence Factor VasX To Kill Dictyostelium discoideum

et al. 2011

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“…For example, effector proteins from the Gram-negative bacteria Vibrio parahaemolyticus and Shigella flexneri display phosphatase activity and can dephosphorylate PIP2 at the membrane of target cells, resulting in blebbing, membrane disruption, and cell lysis (45,46). The sea anemone equinatoxin from Actinia equina also induces membrane blebbing and cell lysis, by inducing Ca 2ϩ -mediated hydrolysis of PIP2 in target cell membranes (47).…”

Section: Discussionmentioning

confidence: 99%

The Tomato Defensin TPP3 Binds Phosphatidylinositol (4,5)-Bisphosphate via a Conserved Dimeric Cationic Grip Conformation To Mediate Cell Lysis

Baxter

Richter

Lay

et al. 2015

Molecular and Cellular Biology

104

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Defensins are a class of ubiquitously expressed cationic antimicrobial peptides (CAPs) that play an important role in innate defense. Plant defensins are active against a broad range of microbial pathogens and act via multiple mechanisms, including cell membrane permeabilization. The cytolytic activity of defensins has been proposed to involve interaction with specific lipid components in the target cell wall or membrane and defensin oligomerization. Indeed, the defensin Nicotiana alata defensin 1 (NaD1) binds to a broad range of membrane phosphatidylinositol phosphates and forms an oligomeric complex with phosphatidylinositol (4,5)-bisphosphate (PIP2) that facilitates membrane lysis of both mammalian tumor and fungal cells. Here, we report that the tomato defensin TPP3 has a unique lipid binding profile that is specific for PIP2 with which it forms an oligomeric complex that is critical for cytolytic activity. Structural characterization of TPP3 by X-ray crystallography and site-directed mutagenesis demonstrated that it forms a dimer in a "cationic grip" conformation that specifically accommodates the head group of PIP2 to mediate cooperative higher-order oligomerization and subsequent membrane permeabilization. These findings suggest that certain plant defensins are innate immune receptors for phospholipids and adopt conserved dimeric configurations to mediate PIP2 binding and membrane permeabilization. This mechanism of innate defense may be conserved across defensins from different species. P lant defensins are small (ϳ5 kDa), cysteine-rich, cationic peptides that belong to the broad class of innate defense molecules known as cationic antimicrobial peptides (CAPs). Plant defensins play a major role in plant innate immunity and have been identified in all analyzed plant species to date, as either constitutively expressed or induced defense molecules that are produced in response to pathogenic attack or environmental stress (1). The tertiary structure of all plant defensins is highly conserved, comprising a triple-stranded antiparallel ␤-sheet and a single ␣-helix stabilized by four disulfide bridges, known as the "cysteine-stabilized alpha-beta" or "CS␣␤" motif (2). Despite this conserved three-dimensional structure, there is a high degree of variation in the primary sequence of plant defensins, particularly at intervening loop regions, which are typically important for activity (3).Many plant defensins have antifungal activity, but other functions have been reported, including antibacterial activity, ion channel blocking, protein synthesis inhibition, and trypsin and ␣-amylase inhibition as well as roles in heavy metal tolerance, plant development, and pollen tube guidance (3-5). They can be divided into two classes based on whether or not a C-terminal propeptide (CTPP) (of ϳ33 amino acids) is present (2, 6). This domain is involved in vacuolar targeting and protects the plant cells from phytotoxicity during transit through the secretory pathway (7). Defensins expressed with the additional CTPP domain are kn...

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“…Vibrio parahaemolyticus can secrete the effector protein VPA0450, a phosphoinositide 5-phosphatase that dephosphorylates PI(4,5)P 2 to PI(4)P, into host cells to induce membrane blebbing and rapid cell lysis. 105 Shigella flexneri can introduce the virulence factor IpgD, a phosphoinositide 4-phosphatase that dephosphorylates PI(4,5)P 2 to PI(5)P, into mammalian cells to aid infection by modulating a variety of host cellular processes, including actin filament remodeling to assist invasion 106 ( Figure 2h) as well as PI3K/Akt/mTOR signaling to inhibit apoptosis and enable bacterial colonization within host cells. 107 Similarly, the Salmonella typhimurium effector molecule SigD, a homolog of Shigella flexneri IpgD, also displays phosphoinositide 4-phosphatase activity towards PI (4,5)P 2 and causes membrane blebbing and cell rounding in infected cells.…”

Section: Pathogenic Entry Via the Host Extracellular Phospholipid Codementioning

confidence: 99%

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

2015

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A significant effort is made by the cell to maintain certain phospholipids at specific sites. It is well described that proteins involved in intracellular signaling can be targeted to the plasma membrane and organelles through phospholipid-binding domains. Thus, the accumulation of a specific combination of phospholipids, denoted here as the 'phospholipid code', is key in initiating cellular processes. Interestingly, a variety of extracellular proteins and pathogen-derived proteins can also recognize or modify phospholipids to facilitate the recognition of dying cells, tumorigenesis and host-microbe interactions. In this article, we discuss the importance of the phospholipid code in a range of physiological and pathological processes.

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A Vibrio Effector Protein Is an Inositol Phosphatase and Disrupts Host Cell Membrane Integrity

Cited by 96 publications

References 20 publications

Vibrio cholerae Requires the Type VI Secretion System Virulence Factor VasX To Kill Dictyostelium discoideum

Vibrio cholerae Requires the Type VI Secretion System Virulence Factor VasX To Kill Dictyostelium discoideum

The Tomato Defensin TPP3 Binds Phosphatidylinositol (4,5)-Bisphosphate via a Conserved Dimeric Cationic Grip Conformation To Mediate Cell Lysis

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

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