Synaptotagmin II Negatively Regulates Ca2+-triggered Exocytosis of Lysosomes in Mast Cells

Baram, Dana; Adachi, Roberto; Medalia, Ora; Tuvim, Michael J.; Dickey, Burton F.; Mekori, Yoseph A.; Sagi‐Eisenberg, Ronit

doi:10.1084/jem.189.10.1649

Cited by 103 publications

(133 citation statements)

References 43 publications

(52 reference statements)

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“…Like ␤-hexosaminidase, cathepsin D is present in lysosome-like secretory granules, as well as conventional lysosomes in mast cells (5). We observed a profound (Ͼ 80%) reduction of cathepsin D release in response to the FcRI cross-linking in VAMP-8-deficient mast cells ( Fig.…”

Section: Deletion Of Vamp-8 Inhibits Serotonin and Cathepsin D Releasmentioning

confidence: 55%

“…For example, FcRI stimulation induces the release of lysosomal hydrolases such as ␤-hexosaminidase and cathepsin D, in addition to the more conventional secretory granule cargo molecules serotonin and histamine (1). Furthermore, in addition to lysosome-like secretory granules, mast cells possess conventional lysosomes that can fuse with the plasma membrane when mast cells receive a strong calcium flux after addition of calcium ionophore or after extensive cross-linking of FcRI (5). Despite the clear difference between lysosome-like secretory granules and conventional lysosomes, it is not known whether there is heterogeneity within the secretory granule population in mast cells.…”

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confidence: 99%

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Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms

Puri

Roche

2008

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

191

189

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Mast cells degranulate and release the contents of intracellular secretory granules in response to the cross-linking of FcRI by multivalent antigens. These granules contain a variety of biologically active inflammatory mediators; however, it is not clear whether these granules are homogenous or whether there is heterogeneity within the secretory granule population in mast cells. By using genetically altered mice lacking specific vesicleassociated SNARE membrane fusion proteins, we found that VAMP-8-deficient mast cells exhibited defects in FcRI-regulated exocytosis, whereas synaptobrevin 2-or VAMP-3-deficient mast cells did not. Surprisingly, the defect in secretion in VAMP-8-deficient mice was limited to the subpopulation of mast cell secretory granules containing serotonin and cathepsin D, whereas regulated exocytosis of secretory granules containing histamine and TNF-␣ was normal. Confocal microscopy confirmed that serotonin and histamine were present in distinct intracellular granules and that most serotonin-containing granules were VAMP-8-positive. Thus, this study demonstrates that mast cells do indeed possess distinct subsets of secretory granules and that these subsets use different SNARE isoforms for exocytosis.serotonin ͉ histamine ͉ VAMP-8

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Section: Deletion Of Vamp-8 Inhibits Serotonin and Cathepsin D Releasmentioning

confidence: 55%

mentioning

confidence: 99%

Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms

Puri

Roche

2008

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

191

189

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“…BLAST analysis reveals that renin and CD are 60% homologous at the amino acid level. Experiments were next performed to ensure that the polyclonal anti-renin Ab did not cross react with CD, which is present in endosomal and lysosomal compartments of mast cells (11,12). We first performed a Western blot analysis using kidney homogenate and pure CD, which were probed with the polyclonal anti-renin Ab (1:12,500) (Fig.…”

Section: Resultsmentioning

confidence: 99%

Mast cells: A unique source of renin

Silver

Reid

Mackins

et al. 2004

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

174

159

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In addition to the traditional renin-angiotensin system, a great deal of evidence favors the existence of numerous independent tissue-specific renin-angiotensin systems. We report that mast cells are an additional source of renin and constitute a unique extrarenal renin-angiotensin system. We use renin-specific antibodies to demonstrate that cardiac mast cells contain renin. Extending this observation to the human mast cell line HMC-1, we show that these mast cells also express renin. The HMC-1 renin RT-PCR product is 100% homologous to Homo sapiens renin. HMC-1 cells also contain renin protein, as demonstrated both by immunoblot and immunocytochemical analyses. Renin released from HMC-1 cells is active; furthermore, HMC-1 cells are able to synthesize renin. It is known that, in the heart, mast cells are found in the interstitium in close proximity to nerves and myocytes, which both express angiotensin II receptors. Inasmuch as myocardial interstitium contains angiotensinogen and angiotensinconverting enzyme, and because we were able to detect renin only in mast cells, we postulate that the release of renin from cardiac mast cells is the pivotal event triggering local formation of angiotensin II. Because of the ubiquity of mast cells, our results represent a unique paradigm for understanding local renin-angiotensin systems, not just in the heart, but in all tissues. Our findings provide a rationale for targeting mast cells in conjunction with renin-angiotensin system inhibitors in the management of angiotensin II-related dysfunctions.T raditionally the renin-angiotensin system (RAS) has been viewed as a circulating axis, whereby renin is released into the circulation from the kidneys in response to decreased renal perfusion pressure, decreased delivery of NaCl at the macula densa, and͞or increased renal sympathetic nerve activity (1). The rate-limiting step in the formation of angiotensin II (ANG II) is the proteolytic action of renin, which cleaves angiotensinogen (Aogen) to the intermediate angiotensin I (ANG I). ANG I is then converted to ANG II by angiotensin-converting enzyme (ACE) at the endothelial surface (2, 3).In addition to this conventional pathway, many tissues, including heart and brain, are thought to be capable of local ANG II production via tissue-specific RAS (4, 5). Although Aogen, ANG I, and ACE, have been demonstrated in various organs, the presence of renin of extrarenal origin has been more difficult to prove and remains controversial. In this investigation, experiments were designed to determine whether renin could be detected in native tissue other than kidney. Because ANG II plays such a crucial role in cardiovascular disease, we focused our efforts on heart tissue, which we screened for renin by using an established polyclonal anti-renin Ab made to recombinant human renin (6). We found that cardiac mast cells were immunopositive for renin. In addition, we used a cultured mast cell line to extrapolate our observations from fixed heart slices to living cells.Our findings indicate that ma...

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“…To further substantiate these results, overexpression of a Syt XI construct diminished levels of secretion and phagocytosis. The role of Syt XI in macrophage trafficking resembles the negative role that Syt II has on the Ca 2+ -dependent exocytosis of lysosomes (48), and on MHC class II presentation in mast cells (49). Although Syt XI and Syt II belong to different Syt subfamilies that have different properties, both of these Syts negatively regulate exocytic processes in cells of the innate immune system.…”

Section: Discussionmentioning

confidence: 99%

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

Duque

Fukuda

Descoteaux

2013

The Journal of Immunology

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Synaptotagmins (Syts) are a group of type I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. All Syts possess a single transmembrane domain, and two conserved tandem Ca2+-binding C2 domains. However, Syts IV and XI possess a conserved serine in their C2A domain that precludes these Syts from binding Ca2+ and phospholipids, and from mediating vesicle fusion. Given the importance of vesicular trafficking in macrophages, we investigated the role of Syt XI in cytokine secretion and phagocytosis. We demonstrated that Syt XI is expressed in murine macrophages, localized in recycling endosomes, lysosomes, and recruited to phagosomes. Syt XI had a direct effect on phagocytosis and on the secretion of TNF and IL-6. Whereas small interfering RNA–mediated knockdown of Syt XI potentiated secretion of these cytokines and particle uptake, overexpression of an Syt XI construct suppressed these processes. In addition, Syt XI knockdown led to decreased recruitment of gp91phox and lysosomal-associated membrane protein–1 to phagosomes, suggesting attenuated microbicidal activity. Remarkably, knockdown of Syt XI ensued in enhanced bacterial survival. Our data reveal a novel role for Syt XI as a regulator of cytokine secretion, particle uptake, and macrophage microbicidal activity.

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Synaptotagmin II Negatively Regulates Ca2+-triggered Exocytosis of Lysosomes in Mast Cells

Cited by 103 publications

References 43 publications

Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms

Mast cells possess distinct secretory granule subsets whose exocytosis is regulated by different SNARE isoforms

Mast cells: A unique source of renin

Synaptotagmin XI Regulates Phagocytosis and Cytokine Secretion in Macrophages

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