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PLOS ONE  2014 

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

DOI: 10.1371/journal.pone.0098900

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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.

References

[1]  Cerwenka A, Lanier LL (2001) Natural killer cells, viruses and cancer. Nat Rev Immunol 1: 41–49. doi: 10.1038/35095564
[2]  Chowdhury D, Lieberman J (2008) Death by a thousand cuts: granzyme pathways of programmed cell death. Annu Rev Immunol 26: 389–420. doi: 10.1146/annurev.immunol.26.021607.090404
[3]  Voskoboinik I, Smyth MJ, Trapani JA (2006) Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol 6: 940–952. doi: 10.1038/nri1983
[4]  Topham NJ, Hewitt EW (2009) Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 128: 7–15. doi: 10.1111/j.1365-2567.2009.03123.x
[5]  de Saint Basile G, Menasche G, Fischer A (2010) Molecular mechanisms of biogenesis and exocytosis of cytotoxic granules. Nat Rev Immunol 10: 568–579. doi: 10.1038/nri2803
[6]  Dustin ML, Long EO (2010) Cytotoxic immunological synapses. Immunol Rev 235: 24–34. doi: 10.1111/j.0105-2896.2010.00904.x
[7]  zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, et al. (2005) Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14: 827–834. doi: 10.1093/hmg/ddi076
[8]  Bryceson YT, Rudd E, Zheng C, Edner J, Ma D, et al. (2007) Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 110: 1906–1915. doi: 10.1182/blood-2007-02-074468
[9]  Danielian S, Basile N, Rocco C, Prieto E, Rossi J, et al. (2010) Novel syntaxin 11 gene (STX11) mutation in three Argentinean patients with hemophagocytic lymphohistiocytosis. J Clin Immunol 30: 330–337. doi: 10.1007/s10875-009-9350-4
[10]  Macartney CA, Weitzman S, Wood SM, Bansal D, Steele M, et al. (2011) Unusual functional manifestations of a novel STX11 frameshift mutation in two infants with familial hemophagocytic lymphohistiocytosis type 4 (FHL4). Pediatr Blood Cancer 56: 654–657. doi: 10.1002/pbc.22676
[11]  Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, et al. (2010) STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer 55: 134–140. doi: 10.1002/pbc.22499
[12]  Cote M, Menager MM, Burgess A, Mahlaoui N, Picard C, et al. (2009) Munc18-2 deficiency causes familial hemophagocytic lymphohistiocytosis type 5 and impairs cytotoxic granule exocytosis in patient NK cells. J Clin Invest 119: 3765–3773. doi: 10.1172/jci40732
[13]  zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, et al. (2009) Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 85: 482–492. doi: 10.1016/j.ajhg.2009.09.005
[14]  Cetica V, Santoro A, Gilmour KC, Sieni E, Beutel K, et al. (2010) STXBP2 mutations in children with familial haemophagocytic lymphohistiocytosis type 5. J Med Genet 47: 595–600. doi: 10.1136/jmg.2009.075341
[15]  Meeths M, Entesarian M, Al-Herz W, Chiang SC, Wood SM, et al. (2010) Spectrum of clinical presentations in familial hemophagocytic lymphohistiocytosis type 5 patients with mutations in STXBP2. Blood 116: 2635–2643. doi: 10.1182/blood-2010-05-282541
[16]  Muller ML, Chiang SC, Meeths M, Tesi B, Entesarian M, et al. (2014) An N-Terminal Missense Mutation in STX11 Causative of FHL4 Abrogates Syntaxin-11 Binding to Munc18-2. Front Immunol 4: 515. doi: 10.3389/fimmu.2013.00515
[17]  Hong W (2005) SNAREs and traffic. Biochim Biophys Acta 1744: 493–517.
[18]  Sudhof TC, Rothman JE (2009) Membrane fusion: grappling with SNARE and SM proteins. Science 323: 474–477. doi: 10.1126/science.1161748
[19]  Prekeris R, Klumperman J, Scheller RH (2000) Syntaxin 11 is an atypical SNARE abundant in the immune system. Eur J Cell Biol 79: 771–780. doi: 10.1078/0171-9335-00109
[20]  Casey TM, Meade JL, Hewitt EW (2007) Organelle proteomics: identification of the exocytic machinery associated with the natural killer cell secretory lysosome. Mol Cell Proteomics 6: 767–780. doi: 10.1074/mcp.m600365-mcp200
[21]  Zhang S, Ma D, Wang X, Celkan T, Nordenskjold M, et al. (2008) Syntaxin-11 is expressed in primary human monocytes/macrophages and acts as a negative regulator of macrophage engulfment of apoptotic cells and IgG-opsonized target cells. Br J Haematol 142: 469–479. doi: 10.1111/j.1365-2141.2008.07191.x
[22]  Valdez AC, Cabaniols JP, Brown MJ, Roche PA (1999) Syntaxin 11 is associated with SNAP-23 on late endosomes and the trans-Golgi network. J Cell Sci 112: 845–854.
[23]  Bin NR, Jung CH, Piggott C, Sugita S (2013) Crucial role of the hydrophobic pocket region of Munc18 protein in mast cell degranulation. Proc Natl Acad Sci U S A 110: 4610–4615. doi: 10.1073/pnas.1214887110
[24]  Xie LX, de la Iglesia-Vicente J, Fang YX, Mollinedo F (2009) Expression and subcellular localization of syntaxin 11 in human neutrophils. Inflamm Res 58: 407–412. doi: 10.1007/s00011-009-0006-x
[25]  Arneson LN, Brickshawana A, Segovis CM, Schoon RA, Dick CJ, et al. (2007) Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol 179: 3397–3401. doi: 10.4049/jimmunol.179.6.3397
[26]  D'Orlando O, Zhao F, Kasper B, Orinska Z, Muller J, et al. (2013) Syntaxin 11 is required for NK and CD8(+) T-cell cytotoxicity and neutrophil degranulation. Eur J Immunol 43: 194–208. doi: 10.1002/eji.201142343
[27]  Ye S, Karim ZA, Al Hawas R, Pessin JE, Filipovich AH, et al. (2012) Syntaxin-11, but not syntaxin-2 or syntaxin-4, is required for platelet secretion. Blood 120: 2484–2492. doi: 10.1182/blood-2012-05-430603
[28]  Hewitt EW, Gupta SS, Lehner PJ (2001) The human cytomegalovirus gene product US6 inhibits ATP binding by TAP. EMBO J 20: 387–396. doi: 10.1093/emboj/20.3.387
[29]  Dabrazhynetskaya A, Ma J, Guerreiro-Cacais AO, Arany Z, Rudd E, et al. (2012) Syntaxin 11 marks a distinct intracellular compartment recruited to the immunological synapse of NK cells to colocalize with cytotoxic granules. J Cell Mol Med 16: 129–141. doi: 10.1111/j.1582-4934.2011.01280.x
[30]  Hackmann Y, Graham SC, Ehl S, Honing S, Lehmberg K, et al. (2013) Syntaxin binding mechanism and disease-causing mutations in Munc18-2. Proc Natl Acad Sci U S A 110: E4482–4491. doi: 10.1073/pnas.1313474110
[31]  Arunachalam L, Han L, Tassew NG, He Y, Wang L, et al. (2008) Munc18-1 is critical for plasma membrane localization of syntaxin1 but not of SNAP-25 in PC12 cells. Mol Biol Cell 19: 722–734. doi: 10.1091/mbc.e07-07-0662
[32]  Han L, Jiang T, Han GA, Malintan NT, Xie L, et al. (2009) Rescue of Munc18-1 and -2 double knockdown reveals the essential functions of interaction between Munc18 and closed syntaxin in PC12 cells. Mol Biol Cell 20: 4962–4975. doi: 10.1091/mbc.e09-08-0712
[33]  Han GA, Malintan NT, Saw NM, Li L, Han L, et al. (2011) Munc18-1 domain-1 controls vesicle docking and secretion by interacting with syntaxin-1 and chaperoning it to the plasma membrane. Mol Biol Cell 22: 4134–4149. doi: 10.1091/mbc.e11-02-0135
[34]  Medine CN, Rickman C, Chamberlain LH, Duncan RR (2007) Munc18-1 prevents the formation of ectopic SNARE complexes in living cells. J Cell Sci 120: 4407–4415. doi: 10.1242/jcs.020230
[35]  Rowe J, Calegari F, Taverna E, Longhi R, Rosa P (2001) Syntaxin 1A is delivered to the apical and basolateral domains of epithelial cells: the role of munc-18 proteins. J Cell Sci 114: 3323–3332.
[36]  Rowe J, Corradi N, Malosio ML, Taverna E, Halban P, et al. (1999) Blockade of membrane transport and disassembly of the Golgi complex by expression of syntaxin 1A in neurosecretion-incompetent cells: prevention by rbSEC1. J Cell Sci 112: 1865–1877.
[37]  Dugan GE, Hewitt EW (2008) Structural and Functional Dissection of the Human Cytomegalovirus Immune Evasion Protein US6. J Virol 82: 3271–3282. doi: 10.1128/jvi.01705-07
[38]  Ren J, Wen L, Gao X, Jin C, Xue Y, et al. (2008) CSS-Palm 2.0: an updated software for palmitoylation sites prediction. Protein Eng Des Sel 21: 639–644. doi: 10.1093/protein/gzn039
[39]  Drisdel RC, Green WN (2004) Labeling and quantifying sites of protein palmitoylation. Biotechniques 36: 276–285.
[40]  Sakurai C, Hashimoto H, Nakanishi H, Arai S, Wada Y, et al. (2012) SNAP-23 regulates phagosome formation and maturation in macrophages. Mol Biol Cell 23: 4849–4863. doi: 10.1091/mbc.e12-01-0069
[41]  Offenhauser C, Lei N, Roy S, Collins BM, Stow JL, et al. (2011) Syntaxin 11 binds Vti1b and regulates late endosome to lysosome fusion in macrophages. Traffic 12: 762–773. doi: 10.1111/j.1600-0854.2011.01189.x
[42]  Linder ME, Deschenes RJ (2007) Palmitoylation: policing protein stability and traffic. Nat Rev Mol Cell Biol 8: 74–84. doi: 10.1038/nrm2084
[43]  Yamaguchi T, Dulubova I, Min SW, Chen X, Rizo J, et al. (2002) Sly1 binds to Golgi and ER syntaxins via a conserved N-terminal peptide motif. Dev Cell 2: 295–305. doi: 10.1016/s1534-5807(02)00125-9
[44]  Furgason ML, MacDonald C, Shanks SG, Ryder SP, Bryant NJ, et al. (2009) The N-terminal peptide of the syntaxin Tlg2p modulates binding of its closed conformation to Vps45p. Proc Natl Acad Sci U S A 106: 14303–14308. doi: 10.1073/pnas.0902976106
[45]  Khvotchev M, Dulubova I, Sun J, Dai H, Rizo J, et al. (2007) Dual modes of Munc18-1/SNARE interactions are coupled by functionally critical binding to syntaxin-1 N terminus. J Neurosci 27: 12147–12155. doi: 10.1523/jneurosci.3655-07.2007
[46]  Burkhardt P, Hattendorf DA, Weis WI, Fasshauer D (2008) Munc18a controls SNARE assembly through its interaction with the syntaxin N-peptide. EMBO J 27: 923–933. doi: 10.1038/emboj.2008.37
[47]  Shen J, Tareste DC, Paumet F, Rothman JE, Melia TJ (2007) Selective activation of cognate SNAREpins by Sec1/Munc18 proteins. Cell 128: 183–195. doi: 10.1016/j.cell.2006.12.016
[48]  Latham CF, Lopez JA, Hu SH, Gee CL, Westbury E, et al. (2006) Molecular dissection of the Munc18c/syntaxin4 interaction: implications for regulation of membrane trafficking. Traffic 7: 1408–1419. doi: 10.1111/j.1600-0854.2006.00474.x
[49]  Vogel K, Roche PA (1999) SNAP-23 and SNAP-25 are palmitoylated in vivo. Biochem Biophys Res Commun 258: 407–410. doi: 10.1006/bbrc.1999.0652
[50]  He Y, Linder ME (2009) Differential palmitoylation of the endosomal SNAREs syntaxin 7 and syntaxin 8. J Lipid Res 50: 398–404. doi: 10.1194/jlr.m800360-jlr200
[51]  Kang R, Wan J, Arstikaitis P, Takahashi H, Huang K, et al. (2008) Neural palmitoyl-proteomics reveals dynamic synaptic palmitoylation. Nature 456: 904–909. doi: 10.1038/nature07605
[52]  Merrick BA, Dhungana S, Williams JG, Aloor JJ, Peddada S, et al. (2011) Proteomic profiling of S-acylated macrophage proteins identifies a role for palmitoylation in mitochondrial targeting of phospholipid scramblase 3. Mol Cell Proteomics 10.1074/mcp.M110.006007.

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