<i>Haemophilus ducreyi</i>
            LspA Proteins Are Tyrosine Phosphorylated by Macrophage-Encoded Protein Tyrosine Kinases

Deng, Kaiping; Mock, Jason R.; Greenberg, Steven M.; Oers, Nicolai S. C. van; Hansen, Eric J.

doi:10.1128/iai.00513-08

Cited by 9 publications

(20 citation statements)

References 48 publications

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“…The EPIYA motifs of B. henselae BepD and BepF, which are delivered into human endothelial cells, also bind to Csk upon tyrosine phosphorylation (16). H. ducreyi inhibits macrophage-mediated phagocytosis, and this inhibition requires an H. ducreyi EPIYA effector, LspA (13,33). By analogy with CagA, it is possible that EPIYA-phosphorylated LspA binds Csk to inhibit SFKs in macrophages.…”

Section: Discussionmentioning

confidence: 99%

Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors

Safari

Murata‐Kamiya

Saito

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Several pathogenic bacteria have adopted effector proteins that, upon delivery into mammalian cells, undergo tyrosine phosphorylation at the Glu-Pro-Ile-Tyr-Ala (EPIYA) or EPIYA-like sequence motif by host kinases such as Src family kinases (SFKs). This EPIYA phosphorylation triggers complex formation of bacterial effectors with SH2 domain-containing proteins that results in perturbation of host cell signaling and subsequent pathogenesis. Although the presence of such an anomalous protein interaction suggests the existence of a mammalian EPIYA-containing protein whose function is mimicked or subverted by bacterial EPIYA effectors, no molecule that uses the EPIYA motif for biological function has so far been reported in mammals. Here we show that mammalian Pragmin/SgK223 undergoes tyrosine phosphorylation at the EPIYA motif by SFKs and thereby acquires the ability to interact with the SH2 domain of the C-terminal Src kinase (Csk), a negative regulator of SFKs. The Pragmin-Csk interaction prevents translocalization of Csk from the cytoplasm to the membrane and subsequent inactivation of membrane-associated SFKs. As a result, SFK activity is sustained in cells where Pragmin is phosphorylated at the EPIYA motif. Because EPIYA phosphorylation of Pragmin is mediated by SFKs, cytoplasmic sequestration of Csk by Pragmin establishes a positive feedback regulation of SFK activation. Remarkably, the Helicobacter pylori EPIYA effector CagA binds to the Csk SH2 domain in place of Pragmin and enforces membrane recruitment of Csk and subsequent inhibition of SFKs. This work identifies Pragmin as a mammalian EPIYA effector and suggests that bacterial EPIYA effectors target Pragmin to subvert SFKs for successful infection. mammalian proteomes | bacterial virulence factors

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Section: Discussionmentioning

confidence: 99%

Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors

Safari

Murata‐Kamiya

Saito

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Specifically, these LspA proteins block Fcg receptor-mediated triggering of phagocytosis by inhibiting SFK activities in host cells (Mock et al, 2005). Both LspA1 and LspA2 are delivered into host cells, where they undergo tyrosine phosphorylation by SFKs (Deng et al, 2008). The LspA proteins contain two 52-amino-acid segments repeated in the mid-region, each of which contains an EPIYA-related EPIYG motif (Fig.…”

Section: Haemophilus Ducreyi Lspa1 and Lspa2mentioning

confidence: 99%

Bacterial EPIYA effectors - Where do they come from? What are they? Where are they going?

Hayashi

Morohashi

Hatakeyama

2012

Cellular Microbiology

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Recent studies have revealed a distinct class of bacterial effectors defined by the presence of EPIYA or EPIYA-related motif. These bacterial EPIYA effectors are delivered into host cells via type III or IV secretion, where they undergo tyrosine phosphorylation at the EPIYA motif and thereby manipulate host signalling by promiscuously interacting with multiple SH2 domain-containing proteins. Up to now, nine EPIYA effectors have been identified from various bacteria. These effectors do not share sequence homology outside the EPIYA motif, arguing against the idea that they have common ancestors. A search of mammalian proteomes revealed the presence of a mammalian EPIYA-containing protein, Pragmin, which potentiates Src family kinase (SFK) activity by binding and sequestrating the SFK inhibitor Csk upon EPIYA phosphorylation. As several bacterial EPIYA effectors also target Csk, they may have evolved through generation of sequences that mimic the Pragmin EPIYA motif. EPIYA motifs are often diverged through multiple duplications in each bacterial effector. Such a structural plasticity appears to be due to intrinsic disorder of the EPIYA-containing region, which enables the bacterial effectors to undergo efficient phosphorylation and mediate promiscuous interaction with multiple host proteins. Given the functional versatility of the EPIYA motif, many more bacterial EPIYA effectors will soon be emerging.

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“…How the LspA proteins enter host cells is unknown. Interestingly, during macrophage- H. ducreyi co-incubations, macrophage kinases tyrosine-phosphorylate LspA proteins [13*]. Although the relevance of tyrosine phosphorylation to the function of LspA1 and LspA2 is unknown, it is intriguing to consider that macrophage-encoded enzymes may activate H. ducreyi -encoded proteins which, in turn, block signalling events in order to shut down phagocytosis.…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Host–pathogen interplay of Haemophilus ducreyi

Janowicz

Bauer

2010

Current Opinion in Infectious Diseases

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Purpose of review Haemophilus ducreyi, the causative agent of the sexually transmitted infection chancroid, is primarily a pathogen of human skin. During infection, H. ducreyi thrives extracellularly in a milieu of professional phagocytes and other antibacterial components of the innate and adaptive immune responses. This review summarizes our understanding of the interplay between this pathogen and its host that leads to development and persistence of disease. Recent findings H. ducreyi expresses key virulence mechanisms to resist host defenses. The secreted LspA proteins are tyrosine-phosphorylated by host kinases, which may contribute to their antiphagocytic effector function. The serum resistance and adherence functions of DsrA map to separate domains of this multifunctional virulence factor. An influx transporter protects H. ducreyi from killing by the antimicrobial peptide LL37. Regulatory genes have been identified that may coordinate virulence factor expression during disease. Dendritic cells and natural killer cells respond to H. ducreyi and may be involved in determining the differential outcomes of infection observed in humans. Summary A human model of H. ducreyi infection has provided insights into virulence mechanisms that allow this human-specific pathogen to survive immune pressures. Components of the human innate immune system may also determine the ultimate fate of H. ducreyi infection by driving either clearance of the organism or an ineffective response that allows disease progression.

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Haemophilus ducreyi LspA Proteins Are Tyrosine Phosphorylated by Macrophage-Encoded Protein Tyrosine Kinases

Cited by 9 publications

References 48 publications

Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors

Mammalian Pragmin regulates Src family kinases via the Glu-Pro-Ile-Tyr-Ala (EPIYA) motif that is exploited by bacterial effectors

Bacterial EPIYA effectors - Where do they come from? What are they? Where are they going?

Host–pathogen interplay of Haemophilus ducreyi

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