title: Syntaxin 11 marks a distinct intracellular compartment recruited to the immunological synapse of NK cells to colocalize with cytotoxic granules.
abstract: The syntaxin 11 (STX11) gene is mutated in a proportion of patients with familial haemophagocytic lymphohistiocytosis (FHL) and exocytosis of cytotoxic granules is impaired in STX11-deficient NK cells. However, the subcellular localization, regulation of expression and molecular function of STX11 in NK cells and other cytotoxic lymphocytes remain unknown. Here we demonstrate that STX11 expression is strictly controlled by several mechanisms in a cell-type-specific manner and that the enzymatic activity of the proteasome is required for STX11 expression in NK cells. In resting NKL cells, STX11 was localized in the cation-dependent mannose-6-phosphate receptor (CD-M6PR)-containing compartment, which was clearly distinct from cytotoxic granules or Rab27a-expressing vesicles. These subcellular structures appeared to fuse at the contact area with NK-sensitive target cells as demonstrated by partial colocalization of STX11 with perforin and Rab27a. Although STX11-deficent allo-specific cytotoxic T-lymphocytes efficiently lysed target cells and released cytotoxic granules, they exhibited a significantly lower extent of spontaneous association of perforin with Rab27a as compared with STX11-expressing T cells. Thus, our results suggest that STX11 promotes the fusion of Rab27a-expressing vesicles with cytotoxic granules and reveal an additional level of complexity in the spatial/temporal segregation of subcellular structures participating in the process of granule-mediated cytotoxicity.
authors.affiliation: Department of Oncology, The Johns Hopkins University School of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: Alena
authors.initials: A
authors.lastname: Dabrazhynetskaya
authors.forename: Jinxia
authors.initials: J
authors.lastname: Ma
authors.forename: Andre Ortlieb
authors.initials: AO
authors.lastname: Guerreiro-Cacais
authors.forename: Zita
authors.initials: Z
authors.lastname: Arany
authors.forename: Eva
authors.initials: E
authors.lastname: Rudd
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Klas
authors.initials: K
authors.lastname: Karre
authors.forename: Jelena
authors.initials: J
authors.lastname: Levitskaya
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
mesh_terms: D002460:Cell Line; D003594:Cytoplasmic Granules / Q000378:metabolism*; D006801:Humans; D054992:Immunological Synapses / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology*; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics / Q000503:physiopathology; D054353:Perforin / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D050765:Qa-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D050765:Qa-SNARE Proteins; D000075745:rab27 GTP-Binding Proteins; D054353:Perforin; D046988:Proteasome Endopeptidase Complex; C066694:RAB27A protein, human; D020691:rab GTP-Binding Proteins