C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]

Publication Date:
2018-07-10
Publisher:
The American Association of Immunologists (AAI)
Print ISSN:
0022-1767
Electronic ISSN:
1550-6606
Topics:
Medicine
Published by:
http://www.aai.org/
_version_ 1836399001260261376
autor Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
beschreibung In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca 2+ -dependent, the molecular identity of the Ca 2+ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca 2+ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca 2+ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca 2+ -dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.
citation_standardnr 6301347
datenlieferant ipn_articles
feed_id 333
feed_publisher The American Association of Immunologists (AAI)
feed_publisher_url http://www.aai.org/
insertion_date 2018-07-10
journaleissn 1550-6606
journalissn 0022-1767
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association of Immunologists (AAI)
quelle Journal of Immunology
relation http://www.jimmunol.org/cgi/content/short/201/2/700?rss=1
search_space articles
shingle_author_1 Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
shingle_author_2 Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
shingle_author_3 Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
shingle_author_4 Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
shingle_catch_all_1 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca 2+ -dependent, the molecular identity of the Ca 2+ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca 2+ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca 2+ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca 2+ -dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.
Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_catch_all_2 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca 2+ -dependent, the molecular identity of the Ca 2+ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca 2+ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca 2+ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca 2+ -dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.
Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_catch_all_3 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca 2+ -dependent, the molecular identity of the Ca 2+ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca 2+ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca 2+ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca 2+ -dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.
Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_catch_all_4 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
In the immune system, degranulation/exocytosis from lymphocytes is crucial for life through facilitating eradication of infected and malignant cells. Dysfunction of the NK cell exocytosis process has been implicated with devastating immune diseases, such as familial hemophagocytic lymphohistiocytosis, yet the underlying molecular mechanisms of such processes have remained elusive. In particular, although the lytic granule exocytosis from NK cells is strictly Ca 2+ -dependent, the molecular identity of the Ca 2+ sensor has yet to be identified. In this article, we show multiple lines of evidence in which point mutations in aspartic acid residues in both C2 domains of human Munc13-4, whose mutation underlies familial hemophagocytic lymphohistiocytosis type 3, diminished exocytosis with dramatically altered Ca 2+ sensitivity in both mouse primary NK cells as well as rat mast cell lines. Furthermore, these mutations within the C2 domains severely impaired NK cell cytotoxicity against malignant cells. Total internal reflection fluorescence microscopy analysis revealed that the mutations strikingly altered Ca 2+ dependence of fusion pore opening of each single granule and frequency of fusion events. Our results demonstrate that both C2 domains of Munc13-4 play critical roles in Ca 2+ -dependent exocytosis and cytotoxicity by regulating single-granule membrane fusion dynamics in immune cells.
Bin, N.-R., Ma, K., Tien, C.-W., Wang, S., Zhu, D., Park, S., Turlova, E., Sugita, K., Shirakawa, R., van der Sluijs, P., Horiuchi, H., Sun, H.-S., Monnier, P. P., Gaisano, H. Y., Sugita, S.
The American Association of Immunologists (AAI)
0022-1767
00221767
1550-6606
15506606
shingle_title_1 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
shingle_title_2 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
shingle_title_3 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
shingle_title_4 C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
timestamp 2025-06-30T23:36:02.139Z
titel C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
titel_suche C2 Domains of Munc13-4 Are Crucial for Ca2+-Dependent Degranulation and Cytotoxicity in NK Cells [MOLECULAR AND STRUCTURAL IMMUNOLOGY]
topic WW-YZ
uid ipn_articles_6301347