A newly identified bacterial cell-penetrating peptide that reduces the transcription of pro-inflammatory cytokines

Rüter, Christian; Buss, Christoph; Scharnert, Julia; Heusipp, Gerhard; Schmidt, M. Alexander

doi:10.1242/jcs.063016

Cited by 55 publications

(85 citation statements)

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“…The ability of fungal and oomycete effectors to enter the host cell independently of the pathogen suggests that they may hijack a plant-derived membrane-transport system or have autonomous membrane-crossing properties. Interestingly, the Yersinia pestis effector protein YopM, which is normally injected into mammalian host cells by the type-III secretion system, was recently shown to also have cell-penetrating properties, with either of the two N-terminal α-helices of YopM capable of autonomous translocation across the cell membrane (35). The structural properties of AvrM, including positive and hydrophobic surface patches required for negatively charged phospholipid binding and uptake, indicate that AvrM has intrinsic membrane-binding properties (7).…”

Section: Discussionmentioning

confidence: 99%

Structures of the flax-rust effector AvrM reveal insights into the molecular basis of plant-cell entry and effector-triggered immunity

Williams

Catanzariti

et al. 2013

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

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Fungal and oomycete pathogens cause some of the most devastating diseases in crop plants, and facilitate infection by delivering a large number of effector molecules into the plant cell. AvrM is a secreted effector protein from flax rust (Melampsora lini) that can internalize into plant cells in the absence of the pathogen, binds to phosphoinositides (PIPs), and is recognized directly by the resistance protein M in flax (Linum usitatissimum), resulting in effector-triggered immunity. We determined the crystal structures of two naturally occurring variants of AvrM, AvrM-A and avrM, and both reveal an L-shaped fold consisting of a tandem duplicated four-helix motif, which displays similarity to the WY domain core in oomycete effectors. In the crystals, both AvrM variants form a dimer with an unusual nonglobular shape. Our functional analysis of AvrM reveals that a hydrophobic surface patch conserved between both variants is required for internalization into plant cells, whereas the C-terminal coiled-coil domain mediates interaction with M. AvrM binding to PIPs is dependent on positive surface charges, and mutations that abrogate PIP binding have no significant effect on internalization, suggesting that AvrM binding to PIPs is not essential for transport of AvrM across the plant membrane. The structure of AvrM and the identification of functionally important surface regions advance our understanding of the molecular mechanisms underlying how effectors enter plant cells and how they are detected by the plant immune system. innate immunity | plant cell internalization | plant disease resistance | avirulence protein | lipid binding F ilamentous eukaryotic microbes such as fungi and oomycetes cause devastating diseases in many economically important crop plants, including rice, corn, wheat, soybean, and potato. During infection, oomycetes and biotrophic fungal pathogens establish a physical interaction with their host through specialized feeding structures, known as haustoria, which facilitate secretion of a vast array of effector proteins to overcome plant defenses and promote host colonization (1-3). The effectors are generally highly divergent even among related species, and generally lack similarity to proteins currently available in the databases, making it difficult to predict biological function from sequence alone. Some of the effectors accumulate in the plant intercellular space (apoplast), whereas others are translocated into the host cell. At present, the host targets and virulence mechanisms of fungal and oomycete effectors are poorly understood. A subset of the planttranslocated effectors called avirulence (Avr) proteins are recognized directly or indirectly and with high specificity by plant disease resistance (R) proteins (4-6). This recognition event leads to activation of effector-triggered immunity (ETI), which usually includes rapid localized host cell death at the site of infectiontermed the hypersensitive response (HR)-and results in the plants being immune to pathogen infection.The question of how...

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Section: Discussionmentioning

confidence: 99%

Structures of the flax-rust effector AvrM reveal insights into the molecular basis of plant-cell entry and effector-triggered immunity

Williams

Catanzariti

et al. 2013

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

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“…In contrast, vaccination of mice with either the YopM type III secretion system protein of Yersinia pestis or the PrpA virulence factor of Brucella abortus does not induce any protective efficacy against bacterial challenge (46,47). Since, in the case of YopM, purified protein can enter into the cell by "autonomous translocation" (48), vaccination with an unmodified form of the protein may preclude the efficient induction of antibodies that neutralize the function of the protein during primary challenge. Similarly, vaccination of mice with a recombinant form of the SSP4 immunomodulatory glycoprotein of Trypanosoma cruzi increases both parasite loads in the blood and lethality following challenge with T. cruzi trypomastigotes, whereas vaccination with an SSP4 cDNA expression plasmid reduces parasitemia and mortality (49).…”

Section: Discussionmentioning

confidence: 99%

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Eberhardt

Deshpande

Chang

et al. 2013

J Virol

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T here is ample precedent from studies of licensed viral and microbial vaccines that vaccine-mediated stimulation of pathogen-specific B cell immunity is critical for protection from infection and/or disease (1). Many new vaccine designs are predicated on the induction of antibodies that neutralize viral attachment to susceptible cells. As phase 2 clinical trials on human cytomegalovirus (HCMV) vaccination have shown, however, this approach only partially protects against challenge virus infection. In one study, seronegative women who had given birth within the previous year were vaccinated against HCMV glycoprotein B (gB) (2), the predominant virion target for antibodies that neutralize infection of fibroblasts. While significant protection against primary HCMV infection was observed in the vaccine group, the effect was limited in magnitude (50%) and duration. In the second placebocontrolled, randomized study, liver and kidney transplant candidates were similarly immunized with gB and prospectively evaluated for parameters of HCMV infection posttransplantation (3). Vaccine-mediated increases in gB-specific antibody titers were inversely correlated with the duration of HCMV viremia posttransplantation. Similar to the trial involving seronegative women, however, vaccination against gB alone in transplant recipients did not completely protect those at risk for HCMV infection.

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“…In this case, pathogen-associated molecular patterns such as lipopolysaccharide (LPS) activated IL-12 production in dendritic cells, which in turn caused IL-10 expression in NK cells (37). Fourth, the penetration of purified recombinant Y. enterocolitica YopM into human HL60-derived macrophage-like cells was not associated with increased transcription levels of IL-10 mRNA after LPS stimulation (43). Therefore, the possibility that the induction of IL-10 is an important virulence function of YopM remains to be established.…”

Section: Y Ersinia Pseudotuberculosis Like the Other Human-pathogenicmentioning

confidence: 99%

Interleukin-10 Induction Is an Important Virulence Function of the Yersinia pseudotuberculosis Type III Effector YopM

et al. 2012

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ABSTRACTPathogenicYersiniaspecies modulate host immune responses through the activity of a plasmid-encoded type III secretion system and its associated effector proteins. One effector, YopM, is a leucine-rich-repeat-containing protein that is important for virulence in murine models ofYersiniainfection. Although the mechanism by which YopM promotes virulence is unknown, we previously demonstrated that YopM was required for the induction of high levels of the immunosuppressive cytokine interleukin-10 (IL-10) in sera of C57BL/6J mice infected withYersinia pseudotuberculosis. To determine if IL-10 production is important for the virulence function of YopM, C57BL/6J or congenic IL-10−/−mice were infected intravenously with wild-type oryopMmutantY. pseudotuberculosisstrains. Analysis of cytokine levels in serum and bacterial colonization in the spleen and liver showed that YopM is required for IL-10 induction in C57BL/6J mice infected with either the IP32953 or the 32777 strain ofY. pseudotuberculosis, demonstrating that the phenotype is conserved in the species. In single-strain infections, the ability of the 32777ΔyopMmutant to colonize the liver was significantly increased by the delivery of exogenous IL-10 to C57BL/6J mice. In mixed infections, the competitive advantage of ayopM+32777 strain over an isogenicyopMmutant to colonize spleen and liver, as observed for C57BL/6J mice, was significantly reduced in IL-10−/−animals. Thus, by experimentally controlling IL-10 levels in a mouse infection model, we obtained evidence that the induction of this cytokine is an important mechanism by which YopM contributes toY. pseudotuberculosisvirulence.

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A newly identified bacterial cell-penetrating peptide that reduces the transcription of pro-inflammatory cytokines

Cited by 55 publications

References 50 publications

Structures of the flax-rust effector AvrM reveal insights into the molecular basis of plant-cell entry and effector-triggered immunity

Structures of the flax-rust effector AvrM reveal insights into the molecular basis of plant-cell entry and effector-triggered immunity

Vaccination against a Virus-Encoded Cytokine Significantly Restricts Viral Challenge

Interleukin-10 Induction Is an Important Virulence Function of the Yersinia pseudotuberculosis Type III Effector YopM

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