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Syntaxin11 serves as a t-SNARE for the fusion of lytic granules in human cytotoxic T lymphocytes
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2014 (English)In: European Journal of Immunology, ISSN 0014-2980, E-ISSN 1521-4141, Vol. 44, no 2Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2014. Vol. 44, no 2
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-298306DOI: 10.1002/eji.201344011ISI: 000331901200027PubMedID: 24227526OAI: oai:DiVA.org:uu-298306DiVA: diva2:945616
Funder
German Research Foundation (DFG), GK1326 SFB894
Available from: 2016-07-01 Created: 2016-07-01 Last updated: 2016-08-01Bibliographically approved

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Marshall, Misty R
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