NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing.
A cytotoxic T lymphocyte (CTL) kills an infected or tumorigenic cell by Ca(2+)-dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. Although inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release from the endoplasmic reticulum activates the stor...
| Hauptverfasser: | , , , , , , , , , , , |
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| Format: | Journal article |
| Sprache: | English |
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2012
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| _version_ | 1826295339878973440 |
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| author | Davis, L Morgan, A Chen, J Snead, C Bloor-Young, D Shenderov, E Stanton-Humphreys, M Conway, S Churchill, G Parrington, J Cerundolo, V Galione, A |
| author_facet | Davis, L Morgan, A Chen, J Snead, C Bloor-Young, D Shenderov, E Stanton-Humphreys, M Conway, S Churchill, G Parrington, J Cerundolo, V Galione, A |
| author_sort | Davis, L |
| collection | OXFORD |
| description | A cytotoxic T lymphocyte (CTL) kills an infected or tumorigenic cell by Ca(2+)-dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. Although inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release from the endoplasmic reticulum activates the store-operated Ca(2+)-influx pathway that is necessary for exocytosis, it is not a sufficient stimulus. Here we identify the Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two-pore channels (TPCs), as being important for T cell receptor signaling in CTLs. We demonstrate that cytolytic granules are not only reservoirs of cytolytic proteins but are also the acidic Ca(2+) stores mobilized by NAADP via TPC channels on the granules themselves, so that TPCs migrate to the immunological synapse upon CTL activation. Moreover, NAADP activates TPCs to drive exocytosis in a way that is not mimicked by global Ca(2+) signals induced by IP(3) or ionomycin, suggesting that critical, local Ca(2+) nanodomains around TPCs stimulate granule exocytosis. Hence, by virtue of the NAADP/TPC pathway, cytolytic granules generate Ca(2+) signals that lead to their own exocytosis and to cell killing. This study highlights a selective role for NAADP in stimulating exocytosis crucial for immune cell function and may impact on stimulus-secretion coupling in wider cellular contexts. |
| first_indexed | 2024-03-07T03:59:31Z |
| format | Journal article |
| id | oxford-uuid:c40f2c20-d2b4-4004-a080-6c7c62a58382 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T03:59:31Z |
| publishDate | 2012 |
| record_format | dspace |
| spelling | oxford-uuid:c40f2c20-d2b4-4004-a080-6c7c62a583822022-03-27T06:20:49ZNAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:c40f2c20-d2b4-4004-a080-6c7c62a58382EnglishSymplectic Elements at Oxford2012Davis, LMorgan, AChen, JSnead, CBloor-Young, DShenderov, EStanton-Humphreys, MConway, SChurchill, GParrington, JCerundolo, VGalione, AA cytotoxic T lymphocyte (CTL) kills an infected or tumorigenic cell by Ca(2+)-dependent exocytosis of cytolytic granules at the immunological synapse formed between the two cells. Although inositol 1,4,5-trisphosphate (IP(3))-mediated Ca(2+) release from the endoplasmic reticulum activates the store-operated Ca(2+)-influx pathway that is necessary for exocytosis, it is not a sufficient stimulus. Here we identify the Ca(2+)-mobilizing messenger nicotinic acid adenine dinucleotide phosphate (NAADP) and its recently identified molecular target, two-pore channels (TPCs), as being important for T cell receptor signaling in CTLs. We demonstrate that cytolytic granules are not only reservoirs of cytolytic proteins but are also the acidic Ca(2+) stores mobilized by NAADP via TPC channels on the granules themselves, so that TPCs migrate to the immunological synapse upon CTL activation. Moreover, NAADP activates TPCs to drive exocytosis in a way that is not mimicked by global Ca(2+) signals induced by IP(3) or ionomycin, suggesting that critical, local Ca(2+) nanodomains around TPCs stimulate granule exocytosis. Hence, by virtue of the NAADP/TPC pathway, cytolytic granules generate Ca(2+) signals that lead to their own exocytosis and to cell killing. This study highlights a selective role for NAADP in stimulating exocytosis crucial for immune cell function and may impact on stimulus-secretion coupling in wider cellular contexts. |
| spellingShingle | Davis, L Morgan, A Chen, J Snead, C Bloor-Young, D Shenderov, E Stanton-Humphreys, M Conway, S Churchill, G Parrington, J Cerundolo, V Galione, A NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. |
| title | NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. |
| title_full | NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. |
| title_fullStr | NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. |
| title_full_unstemmed | NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. |
| title_short | NAADP activates two-pore channels on T cell cytolytic granules to stimulate exocytosis and killing. |
| title_sort | naadp activates two pore channels on t cell cytolytic granules to stimulate exocytosis and killing |
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