A role for endobrevin/VAMP8 in CTL lytic granule exocytosis

Loo, Li Shen; Hwang, Le-Ann; Ong, Yao Min; Tay, Hock Soon; Wang, Cheng-Chun; Hong, Wanjin

doi:10.1002/eji.200939378

Cited by 40 publications

(44 citation statements)

References 18 publications

(29 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In line with this result, it was reported that a knockdown of syntaxin-11 in NK cells reduced their cytotoxic activity, whereas syntaxin-11 overexpression was able to augment cytotoxicity (34). Recently, a reduced exocytosis of lytic granules and an impaired cytotoxic activity of CTL from mice deficient for VAMP8 have been reported (24). We show in this study that Qb-SNARE vti1b is involved in the exocytosis of lytic granules from CTL and confirm this function for the R-SNARE VAMP8.…”

Section: Discussionmentioning

confidence: 55%

See 1 more Smart Citation

The Exocytosis of Lytic Granules Is Impaired in Vti1b- or Vamp8-Deficient CTL Leading to a Reduced Cytotoxic Activity following Antigen-Specific Activation

Dressel

Elsner

Novota

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

The exocytosis of cytotoxic proteins stored in lytic granules of activated CTL is a key event during killing of target cells. Membrane fusion events that are mediated by soluble N-ethylmaleimide-sensitive-factor attachment protein receptor (SNARE) proteins are crucial, as demonstrated by patients with familial hemophagocytic lymphohistocytosis type 4 who have mutations in the SNARE protein syntaxin-11 that result in an impaired degranulation of cytotoxic cells. We found an increased mRNA expression of the SNARE protein genes Vti1b and Vamp8 during Ag-specific activation of CTL from TCR-transgenic OT-I mice. Therefore, we investigated the cytolytic activity of CTL from TCR-transgenic Vti1b and Vamp8 knockout mice. At 3 d as well as at 4 d of Ag-specific stimulation, the degranulation of CTL was significantly reduced in Vti1b and Vamp8 knockout mice, as determined by cell surface expression of the degranulation marker CD107a. After 3 d of Ag-specific stimulation, the cytolytic activity of Vti1b- and Vamp8-deficient CTL was reduced to ≈50% compared with heterozygous controls. However, 4 d after stimulation, the cytotoxic activity of Vti1b- as well as Vamp8-deficient CTL was not impaired anymore. The capacity of Vti1b- and Vamp8-deficient dendritic cells to process Ags and to stimulate the proliferation of CTL was not reduced, arguing against an indirect effect on the activation of CTL. These findings suggest a role of the SNARE proteins vti1b and vesicle-associated membrane protein 8 in the degranulation of CTL. However, a deficiency can apparently be compensated and affects only transiently the cytotoxic activity of CTL during their development to armed effector cells.

show abstract

Section: Discussionmentioning

confidence: 55%

“…In platelets, VAMP8 is involved in exocytosis of dense granules, a granules, and lysosomes (23). Recently, VAMP8 has also been suggested to be involved in granule exocytosis from CTL (24). In addition, VAMP7 has been reported to be essential for granule exocytosis by a NK cell line (25), but its role in primary killer cells has not been determined.…”

mentioning

confidence: 99%

The Exocytosis of Lytic Granules Is Impaired in Vti1b- or Vamp8-Deficient CTL Leading to a Reduced Cytotoxic Activity following Antigen-Specific Activation

Dressel

Elsner

Novota

et al. 2010

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…It is possible that there is substantial divergence in the machinery that controls LG exocytosis in mouse and human cells. However, other groups have observed that VAMP8 colocalizes with LG markers, and Vamp8 knockout mice displayed reduced granule exocytosis and defective cytotoxic activity (65,66). Moreover, a recent study proposed that human CTL cytotoxicity depends on VAMP8-mediated recycling of endosomes at the IS (37), although these fusion events may involve a different set of SNAREs such as VTI1a, VTI1b, STX6, or SNAP29 that we identified as VAMP8 binding partners in Fig.…”

Section: Discussionmentioning

confidence: 67%

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

Spessott

Sanmillan

McCormick

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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 lipidanchored 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.SNARE | Syntaxin 11 | Munc18-2 | CTL | SM protein

show abstract

“…Subsequently it has been shown that VAMP8 is involved in exocytosis in pancreatic acinar cells (16), mast cells (17,18), cytotoxic T lymphocytes (19), platelets (20,21), and kidney collecting duct epithelia (22).…”

mentioning

confidence: 99%

Vesicle-associated Membrane Protein 8 (VAMP8) Is a SNARE (Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor) Selectively Required for Sequential Granule-to-granule Fusion

Behrendorff

Dolai

Hong

et al. 2011

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Compound exocytosis is found in many cell types and is the major form of regulated secretion in acinar and mast cells. Its key characteristic is the homotypic fusion of secretory granules. These then secrete their combined output through a single fusion pore to the outside. The control of compound exocytosis remains poorly understood. Although soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) such as syntaxin 2, SNAP23 (synaptosome-associated protein of 23 kDa), and SNAP25 have been suggested to play a role, none has been proven. Vesicle-associated membrane protein 8 (VAMP8) is a SNARE first associated with endocytic processes but more recently has been suggested as an R-SNARE in regulated exocytosis. Secretion in acinar cells is reduced when VAMP8 function is inhibited and is less in VAMP8 knock-out mice. Based on electron microscopy experiments, it was suggested that VAMP8 may be involved in compound exocytosis. Here we have tested the hypothesis that VAMP8 controls homotypic granule-to-granule fusion during sequential compound exocytosis. We use a new assay to distinguish primary fusion events (fusion with the cell membrane) from secondary fusion events (granule-granule fusion). Our data show the pancreatic acinar cells from VAMP8 knock-out animals have a specific reduction in secondary granule fusion but that primary granule fusion is unaffected. Furthermore, immunoprecipitation experiments show syntaxin 2 association with VAMP2, whereas syntaxin 3 associates with VAMP8. Taken together our data indicate that granule-to-granule fusion is regulated by VAMP8 containing SNARE complexes distinct from those that regulate primary granule fusion.The precise role of compound exocytosis has not been determined, but it is thought that it might enhance secretion by enabling fusion of, and release of contents from, granules that lie deeper within the cell (1). For example, in the case of the massive exocytosis observed during mast cell degranulation (2), compound exocytosis would ensure that secretion occurs both through fusion of granules close to the plasma membrane and from deeper lying granules. This avoids the need to transport deeper granules up to the cell membrane and so would accelerate the secretory response.In the case of acinar cells the apical plasma membrane area is relatively small compared with the total membrane area and is defined by tight junctional boundaries (3). Regulated exocytosis occurs exclusively at the apical membrane. Secretory (zymogen) granules are tightly packed in the apical region of acinar cells (see Fig. 1) and do not move over the minute timescales we use for stimulation. This means that only a few granules have direct access to the apical plasma membrane. Furthermore, granule fusion is so slow (many minutes) that close granules would limit access of deeper-lying granules to docking sites at the plasma membrane. Compound exocytosis provides a mechanism to enhance secretion by enabling deeper granules to fuse with peripheral granules and so release their c...

show abstract

A role for endobrevin/VAMP8 in CTL lytic granule exocytosis

Cited by 40 publications

References 18 publications

The Exocytosis of Lytic Granules Is Impaired in Vti1b- or Vamp8-Deficient CTL Leading to a Reduced Cytotoxic Activity following Antigen-Specific Activation

The Exocytosis of Lytic Granules Is Impaired in Vti1b- or Vamp8-Deficient CTL Leading to a Reduced Cytotoxic Activity following Antigen-Specific Activation

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

Vesicle-associated Membrane Protein 8 (VAMP8) Is a SNARE (Soluble N-Ethylmaleimide-sensitive Factor Attachment Protein Receptor) Selectively Required for Sequential Granule-to-granule Fusion

Contact Info

Product

Resources

About