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Blood, 15 December 2008, Vol. 112, No. 13, pp. 5052-5062. Prepublished online as a Blood First Edition Paper on September 23, 2008; DOI 10.1182/blood-2008-02-141069. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-02-141069v1 112/13/5052    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ménasché, G. Articles by de Saint Basile, G. Search for Related Content PubMed PubMed Citation Articles by Ménasché, G. Articles by de Saint Basile, G. Related Collections Immunobiology Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY A newly identified isoform of Slp2a associates with Rab27a in cytotoxic T cells and participates to cytotoxic granule secretion Gaël Ménasché1,2,*, Mickaël M. Ménager1,2,*, Juliette M. Lefebvre1,2, Einat Deutsch1,2, Rafika Athman1,2, Nathalie Lambert3, Nizar Mahlaoui3, Magali Court4,5,6, Jérôme Garin46, Alain Fischer1,2,3, and Geneviève de Saint Basile13 1 Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Inserm, Unité U768, Paris; 2 Université Paris Descartes, Faculté de Médecine René Descartes, Institut Fédératif de Recherche Necker Enfants-Malades (IFR95), Paris; 3 Unité d'Immunologie-Hématologie Pédiatrique, Assistance Publique-Hôpitaux de Paris, Hôpital Necker Enfants-Malades, Paris; 4 Inserm, Unité U880, Grenoble; 5 Laboratoire d'Etude de la Dynamique des Protéomes, Commissariat à l' Energie Atomique (CEA), DSV, iRTSV, Grenoble; and 6 Université Joseph Fourier, Grenoble, France Cytotoxic T lymphocytes (CTLs) and natural killer cells help control infections and tumors via a killing activity that is mediated by the release of cytotoxic granules. Granule secretion at the synapse formed between the CTL and the target cell leads to apoptosis of the latter. This process involves polarization of the CTL's secretory machinery and cytotoxic granules. The small GTPase Rab27a and the hMunc13-4 protein have been shown to be required for both granule maturation and granule docking and priming at the immunologic synapse. Using a tandem affinity purification technique, we identified a previously unknown hematopoietic form of Slp2a (Slp2a-hem) and determined that it is a specific effector of the active form of Rab27a. This interaction occurs in vivo in primary CTLs. We have shown that (1) Rab27a recruits Slp2a-hem on vesicular structures in peripheral CTLs and (2) following CTL-target cell conjugate formation, the Slp2a-hem/Rab27a complex colocalizes with perforin-containing granules at the immunologic synapse, where it binds to the plasma membrane through its C2 domains. The overexpression of a dominant-negative form of Slp2a-hem markedly impaired exocytosis of cytotoxic granules—indicating that Slp2a is required for cytotoxic granule docking at the immunologic synapse. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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