Syntaxin-11 | ScienceGate

SNARE proteins are known to play a role in regulating intracellular protein transport between donor and target membranes. This docking and fusion process involves the interaction of specific vesicle-SNAREs (e.g. VAMP) with specific cognate target-SNAREs (e.g. syntaxin and SNAP-23). Using human SNAP-23 as the bait in a yeast two-hybrid screen of a human B-lymphocyte cDNA library, we have identified the 287-amino-acid SNARE protein syntaxin 11. Like other syntaxin family members, syntaxin 11 binds to the SNARE proteins VAMP and SNAP-23 in vitro and also exists in a complex with SNAP-23 in transfected HeLa cells and in native human B lymphocytes. Unlike other syntaxin family members, no obvious transmembrane domain is present in syntaxin 11. Nevertheless, syntaxin 11 is predominantly membrane-associated and colocalizes with the mannose 6-phosphate receptor on late endosomes and the trans-Golgi network. These data suggest that syntaxin 11 is a SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network in mammalian cells.

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Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11

Blood ◽

10.1182/blood-2012-07-440339 ◽

2013 ◽

Vol 121 (4) ◽

pp. 595-603 ◽

Cited By ~ 43

Author(s):

Fernando E. Sepulveda ◽

Franck Debeurme ◽

Gaël Ménasché ◽

Mathieu Kurowska ◽

Marjorie Côte ◽

...

Keyword(s):

Macrophage Activation ◽

Late Onset ◽

Lymphocytic Choriomeningitis ◽

Immune Disorder ◽

Genetic Abnormalities ◽

Life Threatening ◽

Syntaxin 11 ◽

Lcmv Infection ◽

Cytotoxic Effector

Abstract Inherited defects of granule-dependent cytotoxicity led to the life-threatening immune disorder hemophagocytic lymphohistiocytosis (HLH), characterized by uncontrolled CD8 T-cell and macrophage activation. In a cohort of HLH patients with genetic abnormalities expected to result in the complete absence of perforin, Rab27a, or syntaxin-11, we found that disease severity as determined by age at HLH onset differed significantly, with a severity gradient from perforin (early onset) > Rab27a > syntaxin-11 (late onset). In parallel, we have generated a syntaxin-11–deficient (Stx11−/−) murine model that faithfully reproduced the manifestations of HLH after lymphocytic choriomeningitis virus (LCMV) infection. Stx11−/− murine lymphocytes exhibited a degranulation defect that could be rescued by expression of human syntaxin-11 but not expression of a C-terminal–truncated mutant. Comparison of the characteristics of LCMV infection-induced HLH in the murine counterparts of the 3 human conditions revealed a similar gradient in the phenotypic severity of HLH manifestations. Strikingly, the severity of HLH was not correlated with the LCMV load and not fully with differences in the intensity of cytotoxic activity. The capacity of antigen presentation differed in vivo between Rab27a- and Syntaxin-11–deficient mutants. Our data indicate that cytotoxic effectors may have other immune-regulatory roles in addition to their role in controlling viral replication.

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C0405: Role of Syntaxin-11 in Granule Release of Neonatal Platelets

Thrombosis Research ◽

10.1016/s0049-3848(14)50090-4 ◽

2014 ◽

Vol 133 ◽

pp. S22

Author(s):

E. Caparrós-Pérez ◽

R. Teruel-Montoya ◽

J.L. Delgado ◽

J.M. Torregrosa ◽

F. Navarro ◽

...

Keyword(s):

Syntaxin 11 ◽

Granule Release

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Defective cytotoxic lymphocyte degranulation in syntaxin-11–deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients

Blood ◽

10.1182/blood-2007-02-074468 ◽

2007 ◽

Vol 110 (6) ◽

pp. 1906-1915 ◽

Cited By ~ 205

Author(s):

Yenan T. Bryceson ◽

Eva Rudd ◽

Chengyun Zheng ◽

Josefine Edner ◽

Daoxin Ma ◽

...

Keyword(s):

Nk Cells ◽

Hemophagocytic Lymphohistiocytosis ◽

Nk Cell ◽

Severe Disease ◽

Target Cells ◽

Loss Of Function ◽

Cytotoxic Lymphocyte ◽

Familial Hemophagocytic Lymphohistiocytosis ◽

Genes Encoding ◽

Syntaxin 11

Abstract Familial hemophagocytic lymphohistiocytosis (FHL) is typically an early onset, fatal disease characterized by a sepsislike illness with cytopenia, hepatosplenomegaly, and deficient lymphocyte cytotoxicity. Disease-causing mutations have been identified in genes encoding perforin (PRF1/FHL2), Munc13-4 (UNC13D/FHL3), and syntaxin-11 (STX11/FHL4). In contrast to mutations leading to loss of perforin and Munc13-4 function, it is unclear how syntaxin-11 loss-of-function mutations contribute to disease. We show here that freshly isolated, resting natural killer (NK) cells and CD8+ T cells express syntaxin-11. In infants, NK cells are the predominant perforin-containing cell type. NK cells from FHL4 patients fail to degranulate when encountering susceptible target cells. Unexpectedly, IL-2 stimulation partially restores degranulation and cytotoxicity by NK cells, which could explain the less severe disease progression observed in FHL4 patients, compared with FHL2 and FHL3 patients. Since the effector T-cell compartment is still immature in infants, our data suggest that the observed defect in NK-cell degranulation may contribute to the pathophysiology of FHL, that evaluation of NK-cell degranulation in suspected FHL patients may facilitate diagnosis, and that these new insights may offer novel therapeutic possibilities.

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Syntaxin 11 Binds Vti1b and Regulates Late Endosome to Lysosome Fusion in Macrophages

Traffic ◽

10.1111/j.1600-0854.2011.01189.x ◽

2011 ◽

Vol 12 (6) ◽

pp. 762-773 ◽

Cited By ~ 40

Author(s):

Carolin Offenhäuser ◽

Nazi Lei ◽

Sandrine Roy ◽

Brett M. Collins ◽

Jennifer L. Stow ◽

...

Keyword(s):

Late Endosome ◽

Syntaxin 11

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SM protein Munc18-2 facilitates transition of Syntaxin 11-mediated lipid mixing to complete fusion for T-lymphocyte cytotoxicity

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1617981114 ◽

2017 ◽

Vol 114 (11) ◽

pp. E2176-E2185 ◽

Cited By ~ 20

Author(s):

Waldo A. Spessott ◽

Maria L. Sanmillan ◽

Margaret E. McCormick ◽

Vineet V. Kulkarni ◽

Claudio G. Giraudo

Keyword(s):

Transmembrane Domain ◽

Snare Complex ◽

Complete Fusion ◽

Sm Proteins ◽

Granule Exocytosis ◽

Cytolytic Granule ◽

Syntaxin 11 ◽

Sm Protein ◽

Lytic Granule

The atypical lipid-anchored Syntaxin 11 (STX11) and its binding partner, the Sec/Munc (SM) protein Munc18-2, facilitate cytolytic granule release by cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Patients carrying mutations in these genes develop familial hemophagocytic lymphohistiocytosis, a primary immunodeficiency characterized by impaired lytic granule exocytosis. However, whether a SNARE such as STX11, which lacks a transmembrane domain, can support membrane fusion in vivo is uncertain, as is the precise role of Munc18-2 during lytic granule exocytosis. Here, using a reconstituted “flipped” cell–cell fusion assay, we show that lipid-anchored STX11 and its cognate SNARE proteins mainly support exchange of lipids but not cytoplasmic content between cells, resembling hemifusion. Strikingly, complete fusion is stimulated by addition of wild-type Munc18-2 to the assay, but not of Munc18-2 mutants with abnormal STX11 binding. Our data reveal that Munc18-2 is not just a chaperone of STX11 but also directly contributes to complete membrane merging by promoting SNARE complex assembly. These results further support the concept that SM proteins in general are part of the core fusion machinery. This fusion mechanism likely contributes to other cell-type–specific exocytic processes such as platelet secretion.

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Characterization of MORN2 stability and regulatory function in LC3-associated phagocytosis in macrophages

Biology Open ◽

10.1242/bio.051029 ◽

2020 ◽

Vol 9 (6) ◽

pp. bio051029 ◽

Cited By ~ 1

Author(s):

Maya Morita ◽

Mayu Kajiye ◽

Chiye Sakurai ◽

Shuichi Kubo ◽

Miki Takahashi ◽

...

Keyword(s):

Membrane Trafficking ◽

Ubiquitin Proteasome System ◽

Snare Proteins ◽

Regulatory Function ◽

Limiting Factor ◽

Sensitive Factor ◽

Protein Receptors ◽

Ubiquitin Proteasome ◽

Syntaxin 11

ABSTRACTMicrotubule-associated protein A1/B1-light chain 3 (LC3)-associated phagocytosis (LAP) is a type of non-canonical autophagy that regulates phagosome maturation in macrophages. However, the role and regulatory mechanism of LAP remain largely unknown. Recently, the membrane occupation and recognition nexus repeat-containing-2 (MORN2) was identified as a key component of LAP for the efficient formation of LC3-recruiting phagosomes. To characterize MORN2 and elucidate its function in LAP, we established a MORN2-overexpressing macrophage line. At a steady state, MORN2 was partially cleaved by the ubiquitin-proteasome system. MORN2 overexpression promoted not only LC3-II production but also LAP phagosome (LAPosome) acidification during Escherichia coli uptake. Furthermore, the formation of LAPosomes containing the yeast cell wall component zymosan was enhanced in MORN2-overexpressing cells and depended on reactive oxygen species (ROS). Finally, MORN2-mediated LAP was regulated by plasma membrane-localized soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) such as SNAP-23 and syntaxin 11. Taken together, these findings demonstrate that MORN2, whose expression is downregulated via proteasomal digestion, is a limiting factor for LAP, and that membrane trafficking by SNARE proteins is involved in MORN2-mediated LAP.

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Syntaxin 11 regulates the stimulus-dependent transport of Toll-like receptor 4 to the plasma membrane by cooperating with SNAP-23 in macrophages

Molecular Biology of the Cell ◽

10.1091/mbc.e18-10-0653 ◽

2019 ◽

Vol 30 (9) ◽

pp. 1085-1097 ◽

Cited By ~ 6

Author(s):

Daiki Kinoshita ◽

Chiye Sakurai ◽

Maya Morita ◽

Masashi Tsunematsu ◽

Naohiro Hori ◽

...

Keyword(s):

Plasma Membrane ◽

Intracellular Transport ◽

Resonance Energy Transfer ◽

Resonance Energy ◽

Interferon Γ ◽

Toll Like Receptor ◽

Toll Like Receptor 4 ◽

Protein Receptor ◽

Syntaxin 11 ◽

Dependent Transport

Syntaxin 11 (stx11) is a soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) that is selectively expressed in immune cells; however, its precise role in macrophages is unclear. We showed that stx11 knockdown reduces the phagocytosis of Escherichia coli in interferon-γ–activated macrophages. stx11 knockdown decreased Toll-like receptor 4 (TLR4) localization on the plasma membrane without affecting total expression. Plasma membrane–localized TLR4 was primarily endocytosed within 1 h by lipopolysaccharide (LPS) stimulation and gradually relocalized 4 h after removal of LPS. This relocalization was significantly impaired by stx11 knockdown. The lack of TLR4 transport to the plasma membrane is presumably related to TLR4 degradation in acidic endosomal organelles. Additionally, an immunoprecipitation experiment suggested that stx11 interacts with SNAP-23, a plasma membrane–localized SNARE protein, whose depletion also inhibits TLR4 replenishment in LPS-stimulated cells. Using an intramolecular Förster resonance energy transfer (FRET) probe for SNAP-23, we showed that the high FRET efficiency caused by LPS stimulation is reduced by stx11 knockdown. These findings suggest that stx11 regulates the stimulus-dependent transport of TLR4 to the plasma membrane by cooperating with SNAP-23 in macrophages. Our results clarify the regulatory mechanisms underlying intracellular transport of TLR4 and have implications for microbial pathogenesis and immune responses.

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