Syntaxin11 serves as a t-SNARE for the fusion of lytic granules in human cytotoxic T lymphocytes.
CTLs kill target cells via fusion of lytic granules (LGs) at the immunological synapse (IS). Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) function as executors of exocytosis. The importance of SNAREs in CTL function is evident in the form of familial hemophagocytic lymphohistiocytosis type 4 that is caused by mutations in Syntaxin11 (Stx11), a Qa-SNARE protein. Here, we investigate the molecular mechanism of Stx11 function in primary human effector CTLs with high temporal and spatial resolution. Downregulation of endogenous Stx11 resulted in a complete inhibition of LG fusion that was paralleled by a reduction in LG dwell time at the IS. Dual color evanescent wave imaging suggested a sequential process, in which first Stx11 is transported to the IS through a subpopulation of recycling endosomes. The resulting Stx11 clusters at the IS then serve as a platform to mediate fusion of arriving LGs. We conclude that Stx11 functions as a t-SNARE for the final fusion of LG at the IS, explaining the severe phenotype of familial hemophagocytic lymphohistiocytosis type 4 on a molecular level.
Institut für Physiologie, Universität des Saarlandes, Homburg/Saar, Germany.
Mahantappa
M
Halimani
Varsha
V
Pattu
Misty R
MR
Marshall
Hsin Fang
HF
Chang
Ulf
U
Matti
Martin
M
Jung
Ute
U
Becherer
Elmar
E
Krause
Markus
M
Hoth
Eva C
EC
Schwarz
Jens
J
Rettig
D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000276:immunology / Q000378:metabolism*; D015536:Down-Regulation / Q000276:immunology; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology / Q000378:metabolism; D051359:Lymphohistiocytosis, Hemophagocytic / Q000276:immunology / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000276:immunology / Q000378:metabolism*; D050600:SNARE Proteins / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
D050765:Qa-SNARE Proteins; D050600:SNARE Proteins; C541732:STX11 protein, human
Cytotoxic T lymphocytes; FHL; Lytic granule fusion; Syntaxin11 clusters; TIRFM