Table 1.
Fusion and fusion accessory proteins in mast cells.
| Group | Name | mRNA | Protein expression | KO model; human deficiency | Subcellular location in mast cells | Functional evidence for a role in mast cell exocytosis | Reference |
|---|---|---|---|---|---|---|---|
| t-SNAREs | SNAP-23 | + | + | KO + (lethal) | PM | SNAP family representative expressed in murine and human MC. Required for release of pre-stored and cytokine/chemokine products. Forms with VAMP8 and STX4 the major SNARE complex in activated RBL-2H3 cells. SNAP-23 siRNA treatment impairs antigen-induced MC degranulation. SNAP-23 inhibition decreases IgE-mediated histamine release in human MC. | Blank (2011), Frank et al. (2011), Sander et al. (2008), Vaidyanathan et al. (2001), Woska and Gillespie (2011) |
| SNAP-25 | + | ± | KO + (lethal) | SG | Human, murine, rat MC (low levels) | Hodel (1998), Salinas et al. (2004), Sander et al. (2008) | |
| STX2 | + | + | ND | Overexpression has no effect on degranulation. Inhibition has no effect on chemokine release. | Paumet et al. (2000), Frank et al. (2011), Sander et al. (2008), Woska and Gillespie (2011) | ||
| STX3 | + | + | SG, PM | Contributes to both SG-PM and SG-SG fusion. Crucial for the release of cytokines/chemokines from mature human MC. Direct binding of complexin II. SNARE complex comprises SNAP-23, STX3, VAMP8, and complexin II. | Frank et al. (2011), Hibi et al. (2000), Paumet et al. (2000), Sander et al. (2008), Tadokoro et al. (2007, 2010), Tiwari et al. (2008) | ||
| STX4 | + | + | KO + (lethal) | PM | Forms with VAMP8 and STX4 the major SNARE complex in activated RBL-2H3 cells. Interacts with SNAP-23, VAMP7, or VAMP8 upon activation of human MC. STX4 inhibition results in decreased IgE-mediated histamine release from human MC. STX4 siRNA treatment impairs antigen-induced MC degranulation. STX4 inhibition decreased release of CXCL8 but not CCL2, CCL3, or CCL4. | Frank et al. (2011), Paumet et al. (2000), Sander et al. (2008), Woska and Gillespie (2011) | |
| STX6 | + | + | ND | Demonstrated in human MC. | Sander et al. (2008) | ||
| v-SNAREs | VAMP2 (synaptobrevin) | + | + | KO+ | SG | Low levels in human MC. Minor colocalization with SG, relocation from SG to PM in activated MC. VAMP2 siRNA does not modulate RBL-2H3 cell degranulation. Compensatory effect through enhanced SNAP-23 – VAMP2 complex formation in activated VAMP8−/− derived MC. | Puri and Roche (2008), Sander et al. (2008), Tiwari et al. (2008), Woska and Gillespie (2011) |
| VAMP3 | + | + | KO+ | Vesicular, SG | Substantial amounts in human MC. Minor colocalization with SG; major relocation to PM in IL-1beta stimulated MC in absence of degranulation Peripheral VAMP3 colocalizes with exocytosed TNF at the cell surface. No effect on chemokine release. No effect on IgE-mediated histamine release. | Frank et al. (2011), Paumet et al. (2000), Puri and Roche (2008), Sander et al. (2008), Tiwari et al. (2008) | |
| VAMP7 | + | + | KO+ | Vesicular | Substantial amounts in human MC. Minor colocalization with SG. Relocation to PM in activated MC. Interacts with SNAP-23 and STX4 in activated MC. VAMP7 inhibition decreases IgE-mediated histamine release from human MC. VAMP7 siRNA treatment impairs IgE-induced MC degranulation. | Hibi et al. (2000), Sander et al. (2008), Tiwari et al. (2008), Woska and Gillespie (2011) | |
| VAMP8 (endobrevin) | + | + | KO+ | Vesicular, SG | Substantial amounts in human MC. Localizes to endosomes, but also major colocalization with SG. Relocation to PM upon MC activation. VAMP8−/− MC display impaired degranulation of pre-stored mediators in vitro and in vivo, but normal cytokine and chemokine production. Forms increased complexes with SNAP-23 and STX4 after stimulation. Specific cytokine/chemokine release by IL-1beta stimulation in the absence of degranulation does not induce VAMP8 relocation to PM. | Frank et al. (2011), Paumet et al. (2000), Hibi et al. (2000), Puri and Roche (2008), Sander et al. (2008), Tadokoro et al. (2010), Tiwari et al. (2008), Woska and Gillespie (2011) | |
| Accessory proteins | Rab3A | + | + | Cytoplasmic | Overexpression: either null or inhibitory effect on activated MC exocytosis. | Roa et al. (1997), Smith et al. (1997) | |
| Rab3B | + | + | ND | ND | Oberhauser et al. (1992) | ||
| Rab3D | + | + | KO+ | SG, others | Relocation to PM upon MC activation. May regulate SNARE assembly via Rak3D-mediated phosphorylation of STX4. Rab3D deficiency does not impair exocytosis in patch clamp activated MC. Rab3D deficiency is associated with abnormally large SG, suggesting a role for Rab3D in preventing granule fusion. | Blank et al. (2002), Pombo et al. (2001), Roa et al. (1997), Riedel et al. (2002), Tuvim et al. (1999) | |
| Rab27a | + | + | KO+ | Cytoplasmic, SG? | Might operate the transition from microtubule-driven granule mobility to actin-based exocytosis. | Goishi et al. (2004), Mizuno et al. (2007) | |
| Rab27b | + | + | KO+ | Cytoplasmic, SG? | Double KO and to a lesser extent single KO animals display impaired passive cutaneous anaphylaxis responses. Bone marrow-derived MC from double/single KO animals show a decrease in antigen-induced histamine release. | ||
| Munc18-1 | + | − | KO + (lethal) | ND | Nigam et al. (2005) | ||
| Munc18-2 | + | + | Human: FHL-5 | SG | Negative regulators of SNARE assembly through binding to non-complexed syntaxins. Fusion promoters through binding to trans-SNARE complexes. Relocation to lamellipodia. Overexpression inhibits exocytosis in activated MC. | Martin-Verdeaux et al. (2003), Pombo et al. (2003), Tadokoro et al. (2007) | |
| Munc18-3 | + | + | KO + (lethal) | PM | Overexpression does not alter MC exocytosis | Martin-Verdeaux et al. (2003) | |
| Munc13-4 | + | + | Human: FHL3 | SG | Positive regulator of MC degranulation. Overexpression enhances activated MC exocytosis. | Neeft et al. (2005) | |
| SCAMP-1, -2, -3 | ND | + | SG, PM | Colocalization at PM between SCAMPs, STX4, and SNAP-23. SCAMPs may serve as targets for SNAP-23 relocation, then contribute to the formation of the fusion pore. | Castle et al. (2002) | ||
| Complexin II | + | + | KO+ | Cytoplasmic | Relocation to PM in activated MC. Complexin II siRNA inhibits exocytosis. Interacts with a SNARE complex comprising SNAP-23, STX3, and VAMP2 or VAMP8. Direct binding to STX3 and to VAMP8 but not to SNAP-23. | Tadokoro et al. (2005, 2010), Takahashi et al. (1999) | |
| Synaptotagmin I | − | − | SG (exogenous) | Exogenously expressed synaptotagmin I enhances calcium ionophore-activated MC exocytosis. | Baram et al. (1998), Kimura et al. (2001) | ||
| Synaptotagmin II | + | + | KO+ | Lysosomes | Most abundant MC synaptotagmin. Required for degranulation and cell surface expression of MHC class II molecules. Synaptotagmin II siRNA enhances fusion of genuine lysosomes with SG. Synaptotagmin II KO mice: impaired passive cutaneous anaphylaxis, impaired MC degranulation. | Baram et al. (1999), Melicoff et al. (2009), Nagai et al. (2011), Peng et al. (2002) | |
| Synaptotagmin III | + | + | Early endosomes, SG | Synaptotagmin III antisense cDNA treated RBL cells display impaired function of the endocytic recycling compartment and enlarged SG size | Grimberg et al. (2003) | ||
| Synaptotagmin IX | + | + | Endocytic recycling compartment, PM | Protein export from the endocytic recycling compartment toward PM. Sorting of SG proteins. Synaptotagmin IX siRNA slows down protein export from the endocytic recycling compartment to the cell surface. | Haberman et al. (2003, 2007) | ||
| NCS-1 | + | + | Stimulation of Fc epsilon receptor (through enhanced endocytic recycling) but not calcium ionophore induced exocytosis. | Kapp-Barnea et al. (2003, 2006) |
Abbreviations: FHL, familial human lymphohistiocytosis; KO, knock-out; ND, not determined; MC, mast cells; NCS, neuronal calcium sensor; PM, plasma membrane; SG, secretory granules; STX, syntaxin.