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Synaptotagmin Xl, a negative regulator of cytokine secretion and phagocytosis, is targeted by GP63

Arango Duque, Guillermo; Fukuda, Mitsunori; Descoteaux, Albert . Synaptotagmin Xl, a negative regulator of cytokine secretion and phagocytosis, is targeted by GP63 In: 12ième Symposium Annuel de Parasitologie Moléculaire du Québec, 28-29 mai 2012, INRS- Institut Armand-Frapper, Laval, Qc, Canada.

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Résumé

Leishmania parasites infect phagocytic cells, especially macrophages. An important pathogenesis factor in Leishmania is the GP63 metalloprotease. GP63 alters multiple modules of macrophage signalling and cleaves components of the vesicle fusion machinery, ensuing in weakened antimicrobicidal responses. Synaptotagmins (Syts) are membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. Syts possess a transmembrane domain, and two conserved tandem Ca2 +binding C2 domains. However, Syts IV and Xl possess a conserved serine in their C2A domain that precludes these Syts from binding ci•, and from mediating vesicle fusion. Given the importance of vesicular trafficking in macrophages, the objective of this research was to elucidate the rote of Syt Xl in cytokine secretion and phagocytosis, and to investigate the impact of GP63 on Syt Xl function. We demonstrated that Syt is expressed in macrophages, localized in transferrin receptor 1-containing recycling endosomes, and recruited to early phagosomes. Syt Xl had a direct effect on the secretion of tumour necrosis factor (TNF) and interleukin 6 (IL-6), and on phagocytosîs. Whereas siRNA-mediated knockdown of Syt Xl potentiated secretion of the se cytokines and particle uptake, overexpression of a Syt Xl construct suppressed these processes. On the other hand, Syt Xl was not recruited to phagosomes containing L. major promastigotes expressing GP63. Upon finding that GP63 caused Syt Xl degradation and augmented the release of TNF and ll-6, we showed th at secretion of these cytokines depended on Syt Xl degradation. Altogether, our data reveal novel rotes for Syt Xl, and provîde a mechanism by whîch Leishmania induces the secretion of proinflammatory cytokines.

Type de document: (NON SPÉCIFIÉ)
Mots-clés libres: -
Centre: Centre INRS-Institut Armand Frappier
Date de dépôt: 05 juill. 2017 20:25
Dernière modification: 05 juill. 2017 20:25
URI: http://espace.inrs.ca/id/eprint/5688

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