title: Different Munc13 isoforms function as priming factors in lytic granule release from murine cytotoxic T lymphocytes.
abstract: In order to fuse lytic granules (LGs) with the plasma membrane at the immunological synapse, cytotoxic T lymphocytes (CTLs) have to render these LGs fusion-competent through the priming process. In secretory tissues such as brain and neuroendocrine glands, this process is mediated by members of the Munc13 protein family. In human CTLs, mutations in the Munc13-4 gene cause a severe loss in killing efficiency, resulting in familial hemophagocytic lymphohistiocytosis type 3, suggesting a similar role of other Munc13 isoforms in the immune system. Here, we investigate the contribution of different Munc13 isoforms to the priming process of murine CTLs at both the mRNA and protein level. We demonstrate that Munc13-1 and Munc13-4 are the only Munc13 isoforms present in mouse CTLs. Both isoforms rescue the drastical secretion defect of CTLs derived from Munc13-4-deficient Jinx mice. Mobility studies using total internal reflection fluorescence microscopy indicate that Munc13-4 and Munc13-1 are responsible for the priming process of LGs. Furthermore, the domains of the Munc13 protein, which is responsible for functional fusion, could be identified. We conclude from these data that both isoforms of the Munc13 family, Munc13-1 and Munc13-4, are functionally redundant in murine CTLs.
authors.affiliation: Institut für Physiologie, Universität des Saarlandes, Kirrberger Str. 8, 66421 Homburg/Saar, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Dudenhöffer-Pfeifer
authors.forename: Claudia
authors.initials: C
authors.lastname: Schirra
authors.forename: Varsha
authors.initials: V
authors.lastname: Pattu
authors.forename: Mahantappa
authors.initials: M
authors.lastname: Halimani
authors.forename: Monika
authors.initials: M
authors.lastname: Maier-Peuschel
authors.forename: Misty R
authors.initials: MR
authors.lastname: Marshall
authors.forename: Ulf
authors.initials: U
authors.lastname: Matti
authors.forename: Ute
authors.initials: U
authors.lastname: Becherer
authors.forename: Jan
authors.initials: J
authors.lastname: Dirks
authors.forename: Martin
authors.initials: M
authors.lastname: Jung
authors.forename: Peter
authors.initials: P
authors.lastname: Lipp
authors.forename: Markus
authors.initials: M
authors.lastname: Hoth
authors.forename: Martina
authors.initials: M
authors.lastname: Sester
authors.forename: Elmar
authors.initials: E
authors.lastname: Krause
authors.forename: Jens
authors.initials: J
authors.lastname: Rettig
mesh_terms: D000818:Animals; D005089:Exocytosis; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D022142:Secretory Vesicles / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C503321:Unc13a protein, mouse; C520225:Unc13d protein, mouse