Abstract
Abstract Cytotoxic T Lymphocytes (CTLs) and Natural Killer (NK) cells selectively kill virally infected or cancer cells by releasing the content of lytic granules at the contact area with target cells called immunological synapse (IS). SNAREs mediate the maturation and exocytosis of “fully-armed” lytic granules at the IS. Deregulation of SNARE-mediated fusion events, such as in Familial Hemophagocytic Lymphohystiocytosis-4 and -5, in which Syntaxin11 and Syntaxin Binding Protein-2 are mutated, respectively; severely impaired lytic granule release and cytotoxicity of CTL and NK-cells. We have identified cognate SNAREs that specifically interact with Syntaxin11 to perform its function during CTL activation and lytic granule release. Biochemical experiments showed that these interacting proteins can form stable SNARE complexes and confirmed the specificity of these interactions. Stimulated Emission Depletion (STED) Superresolution microscopy studies revealed two pools of Syntaxin 11 in CTLs, one localized to a M6PR-containing vesicular compartment, and one localized at the plasma membrane. We have precisely visualized the localization patterns Sytanxin11-interacting partners and other membrane trafficking proteins involved in this process. These results support the conclusion that the identified Syntaxin11-containing SNARE complex plays a crucial role during CTL-mediated cytotoxicity and FHL pathophysiology.
Published Version
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