A newly identified isoform of Slp2a associates with Rab27a in cytotoxic T cells and participates to cytotoxic granule secretion.
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.
Ménasché
Gaël
G
Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Inserm, Unité U768, Paris, France.
Ménager
Mickaël M
MM
Lefebvre
Juliette M
JM
Deutsch
Einat
E
Athman
Rafika
R
Lambert
Nathalie
N
Mahlaoui
Nizar
N
Court
Magali
M
Garin
Jérôme
J
Fischer
Alain
A
de Saint Basile
Geneviève
G
D005089:Exocytosis; D054992:Immunological Synapses; D008565:Membrane Proteins / Q000378:metabolism*; D020033:Protein Isoforms; D021381:Protein Transport; D022142:Secretory Vesicles / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
D008565:Membrane Proteins; D020033:Protein Isoforms; C486043:SYTL2 protein, human; D000075745:rab27 GTP-Binding Proteins; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins