title: Analysis of familial hemophagocytic lymphohistiocytosis type 4 (FHL-4) mutant proteins reveals that S-acylation is required for the function of syntaxin 11 in natural killer cells.
abstract: Natural killer (NK) cell secretory lysosome exocytosis and cytotoxicity are impaired in familial hemophagocytic lymphohistiocytosis type 4 (FHL-4), a disorder caused by mutations in the gene encoding the SNARE protein syntaxin 11. We show that syntaxin 11 binds to SNAP23 in NK cells and that this interaction is reduced by FHL-4 truncation and frameshift mutation proteins that delete all or part of the SNARE domain of syntaxin 11. In contrast the FHL-4 mutant proteins bound to the Sec-1/Munc18-like (SM) protein Munc18-2. We demonstrate that the C-terminal cysteine rich region of syntaxin 11, which is deleted in the FHL-4 mutants, is S-acylated. This posttranslational modification is required for the membrane association of syntaxin 11 and for its polarization to the immunological synapse in NK cells conjugated to target cells. Moreover, we show that Munc18-2 is recruited by syntaxin 11 to intracellular membranes in resting NK cells and to the immunological synapse in activated NK cells. This recruitment of Munc18-2 is abolished by deletion of the C-terminal cysteine rich region of syntaxin 11. These results suggest a pivotal role for S-acylation in the function of syntaxin 11 in NK cells.
authors.affiliation: School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Hellewell
authors.affiliation: School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Ombretta
authors.initials: O
authors.lastname: Foresti
authors.affiliation: School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gover
authors.affiliation: School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Morwenna Y
authors.initials: MY
authors.lastname: Porter
authors.affiliation: School of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds, United Kingdom.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hewitt
mesh_terms: D000215:Acylation; D001483:Base Sequence; D003545:Cysteine / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D054992:Immunological Synapses; D007425:Intracellular Membranes / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology* / Q000378:metabolism; D051359:Lymphohistiocytosis, Hemophagocytic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D050505:Mutant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050765:Qa-SNARE Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D050766:Qb-SNARE Proteins / Q000378:metabolism; D050767:Qc-SNARE Proteins / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D050765:Qa-SNARE Proteins; D050766:Qb-SNARE Proteins; D050767:Qc-SNARE Proteins; C100493:SNAP23 protein, human; D003545:Cysteine