The major surface protease (MSP or GP63) in the intracellular amastigote stage of Leishmania chagasi

Hsiao, Chia‐Hung Christine; Yao, Chaoqun; Storlie, Patricia; Donelson, John E.; Wilson, Mary E.

doi:10.1016/j.molbiopara.2007.10.008

Cited by 38 publications

(59 citation statements)

References 64 publications

(85 reference statements)

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“…2D), we observed that L. donovani amastigotes did not induce Syt XI degradation (Fig. 2C) (18,56). Similarly, infection with promastigotes of the nonpathogenic L. tarentolae species did not lead to Syt XI degradation (Fig.…”

Section: Resultsmentioning

confidence: 69%

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Duque

Fukuda

Turco

et al. 2014

The Journal of Immunology

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Synaptotagmins (Syts) are type-I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. We recently discovered that Syt XI is a recycling endosome- and lysosome-associated protein that negatively regulates the secretion of TNF and IL-6. In this study, we show that Syt XI is directly degraded by the zinc metalloprotease GP63 and excluded from Leishmania parasitophorous vacuoles by the promastigotes surface glycolipid lipophosphoglycan. Infected macrophages were found to release TNF and IL-6 in a GP63-dependent manner. To demonstrate that cytokine release was dependent on GP63-mediated degradation of Syt XI, small interfering RNA-mediated knockdown of Syt XI before infection revealed that the effects of small interfering RNA knockdown and GP63 degradation were not cumulative. In mice, i.p. injection of GP63-expressing parasites led to an increase in TNF and IL-6 secretion and to an augmented influx of neutrophils and inflammatory monocytes to the inoculation site. Both of these cell types have been shown to be infection targets and aid in the establishment of infection. In sum, our data revealed that GP63 induces proinflammatory cytokine release and increases infiltration of inflammatory phagocytes. This study provides new insight on how Leishmania exploits the immune response to establish infection.

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Section: Resultsmentioning

confidence: 69%

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Duque

Fukuda

Turco

et al. 2014

The Journal of Immunology

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“…1D), implying that GP63-mediated downmodulation of Wnt5a protein level is a possibility during infection of macrophages by L. donovani promastigotes and amastigotes. Because of probable differences in the cellular distributions of GP63 in promastigotes versus amastigotes (32), the modes of GP63-mediated reduction of Wnt5a protein by L. donovani promastigotes and amastigotes may be different. Involvement of phenanthroline-inhibitable metalloproteases other than GP63 in the downmodulation of Wnt5a protein levels is also possible (33).…”

Section: Donovani Infection Leads To Disruption Of the Steady-statmentioning

confidence: 99%

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

Chakraborty

Kurati

Mahata

et al. 2017

The Journal of Immunology

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Leishmania donovani infects macrophages, disrupting immune homeostasis. The underlying mechanism that sustains infection remains unresolved. In view of the potential of Wnt5a signaling to support immune homeostasis, we evaluated the interrelationship of Wnt5a signaling and Leishmania donovani infection. Upon infecting macrophages separately with antimony drug–sensitive and –resistant L. donovani, we noted disruption in the steady-state level of Wnt5a. Moreover, inhibition of Wnt5a signaling by small interfering RNA transfection in vitro or by use of inhibitor of Wnt production in vivo led to an increase in cellular parasite load. In contrast, treatment of macrophages with recombinant Wnt5a caused a decrease in the load of antimony-sensitive and -resistant parasites, thus confirming that Wnt5a signaling antagonizes L. donovani infection. Using inhibitors of the Wnt5a signaling intermediates Rac1 and Rho kinase, we demonstrated that Wnt5a-mediated inhibition of parasite infection in macrophages is Rac1/Rho dependent. Furthermore, phalloidin staining and reactive oxygen species estimation of Wnt5a-treated macrophages suggested that a Wnt5a-Rac/Rho–mediated decrease in parasite load is associated with an increase in F- actin assembly and NADPH oxidase activity. Moreover, live microscopy of L. donovani–infected macrophages treated with Wnt5a demonstrated increased endosomal/lysosomal fusions with parasite-containing vacuoles (parasitophorous vacuoles [PV]). An increase in PV–endosomal/lysosomal fusion accompanied by augmented PV degradation in Wnt5a-treated macrophages was also apparent from transmission electron microscopy of infected cells. Our results suggest that, although L. donovani evades host immune response, at least in part through inhibition of Wnt5a signaling, revamping Wnt5a signaling can inhibit L. donovani infection, irrespective of drug sensitivity or resistance.

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“…Moreover, similar to fibronectin, coating polystyrene surfaces with GP63 enhances in vitro spreading of fibroblasts (42). The expression of specific gp63 genes in the intracellular amastigote form (27,43,44) implies an intra-host cell function for this parasitic protease. Interestingly, the activity of GP63 was implicated in the protection of encapsulated proteins against phagolysosomal degradation as well as intra-macrophage survival of Leishmania mexicana amazonensis (45,46).…”

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confidence: 99%

The Leishmania Surface Protease GP63 Cleaves Multiple Intracellular Proteins and Actively Participates in p38 Mitogen-activated Protein Kinase Inactivation

Hallé

Gómez

Stuible

et al. 2009

Journal of Biological Chemistry

127

107

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The Leishmania parasite is a widespread disease threat in tropical areas, causing symptoms ranging from skin lesions to death. Leishmania parasites typically invade macrophages but are also capable of infecting fibroblasts, which may serve as a reservoir for recurrent infection. Invasion by intracellular pathogens often involves exploitation of the host cell cytoskeletal and signaling machinery. Here we have observed a dramatic rearrangement of the actin cytoskeleton and marked modifications in the profile of protein tyrosine phosphorylation in fibroblasts infected with Leishmania major. Correspondingly, exposure to L. major resulted in degradation of the phosphorylated adaptor protein p130Cas and the protein-tyrosine phosphatase-PEST. Cellular and in vitro assays using pharmacological protease inhibitors, recombinant enzyme, and genetically modified strains of L. major identified the parasite protease GP63 as the principal catalyst of proteolysis during infection. A number of additional signaling proteins were screened for degradation during L. major infection as follows: a small subset was cleaved, including cortactin, T-cell protein-tyrosine phosphatase, and caspase-3, but the majority remained unaffected. Protein degradation occurred in cells incubated with Leishmania extracts in the absence of intact parasites, suggesting a mechanism permitting transfer of functional GP63 into the intracellular space. Finally, we evaluated the impact of Leishmania on MAPK signaling; unlike p44/42 and JNK, p38 was inactivated upon infection in a GP63-and protein degradation-dependent manner, which likely involves cleavage of the upstream adaptor TAB1. Our results establish that GP63playsacentralroleinanumberofhostcellmoleculareventsthat likely contribute to the infectivity of Leishmania.

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The major surface protease (MSP or GP63) in the intracellular amastigote stage of Leishmania chagasi

Cited by 38 publications

References 64 publications

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Leishmania Promastigotes Induce Cytokine Secretion in Macrophages through the Degradation of Synaptotagmin XI

Wnt5a Signaling Promotes Host Defense againstLeishmania donovaniInfection

The Leishmania Surface Protease GP63 Cleaves Multiple Intracellular Proteins and Actively Participates in p38 Mitogen-activated Protein Kinase Inactivation

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