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Different Munc13 Isoforms Function as Priming Factors in Lytic Granule Release from Murine Cytotoxic T Lymphocytes
Author(s) -
DudenhöfferPfeifer Monika,
Schirra Claudia,
Pattu Varsha,
Halimani Mahantappa,
MaierPeuschel Monika,
Marshall Misty R.,
Matti Ulf,
Becherer Ute,
Dirks Jan,
Jung Martin,
Lipp Peter,
Hoth Markus,
Sester Martina,
Krause Elmar,
Rettig Jens
Publication year - 2013
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/tra.12074
Subject(s) - lytic cycle , cytotoxic t cell , biology , priming (agriculture) , microbiology and biotechnology , immunological synapse , gene isoform , immune system , secretion , immunology , t cell , gene , virus , in vitro , t cell receptor , biochemistry , botany , germination
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.