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Titel: Role of V-ATPase a3-Subunit in Mouse CTL Function
VerfasserIn: Chitirala, Praneeth
Ravichandran, Keerthana
Schirra, Claudia
Chang, Hsin-Fang
Krause, Elmar
Kazmaier, Uli
Lauterbach, Marcel A.
Rettig, Jens
Sprache: Englisch
Titel: The Journal of Immunology
Bandnummer: 204
Heft: 10
Seiten: 2818–2828
Verlag/Plattform: American Association of Immunology
Erscheinungsjahr: 2020
DDC-Sachgruppe: 610 Medizin, Gesundheit
Dokumenttyp: Journalartikel / Zeitschriftenartikel
Abstract: CTLs release cytotoxic proteins such as granzymes and perforin through fusion of cytotoxic granules (CG) at the target cell interface, the immune synapse, to kill virus-infected and tumorigenic target cells. A characteristic feature of these granules is their acidic pH inside the granule lumen, which is required to process precursors of granzymes and perforin to their mature form. However, the role of acidic pH in CG maturation, transport, and fusion is not understood. We demonstrate in primary murine CTLs that the a3-subunit of the vacuolar-type (H+)–adenosine triphosphatase is required for establishing a luminal pH of 6.1 inside CG using ClopHensorN(Q69M), a newly generated CG-specific pH indicator. Knockdown of the a3-subunit resulted in a significantly reduced killing of target cells and a >50% reduction in CG fusion in total internal reflection fluorescence microscopy, which was caused by a reduced number of CG at the immune synapse. Superresolution microscopy revealed a reduced interaction of CG with the microtubule network upon a3-subunit knockdown. Finally, we find by electron and structured illumination microscopy that knockdown of the a3-subunit altered the diameter and density of individual CG, whereas the number of CG per CTL was unaffected. We conclude that the a3-subunit of the vacuolar adenosine triphosphatase is not only responsible for the acidification of CG, but also contributes to the maturation and efficient transport of the CG to the immune synapse.
DOI der Erstveröffentlichung: 10.4049/jimmunol.1901536
URL der Erstveröffentlichung: http://dx.doi.org/10.4049/jimmunol.1901536
Link zu diesem Datensatz: urn:nbn:de:bsz:291--ds-383947
hdl:20.500.11880/34653
http://dx.doi.org/10.22028/D291-38394
ISSN: 1550-6606
0022-1767
Datum des Eintrags: 6-Dez-2022
Bezeichnung des in Beziehung stehenden Objekts: Supplementary data
In Beziehung stehendes Objekt: https://journals.aai.org/jimmunol/article-supplement/110088/pdf/ji_1901536_supplemental_figures_1/
Fakultät: M - Medizinische Fakultät
NT - Naturwissenschaftlich- Technische Fakultät
Fachrichtung: M - Physiologie
NT - Chemie
Professur: M - Prof. Dr. Jens Rettig
NT - Prof. Dr. Uli Kazmaier
Sammlung:SciDok - Der Wissenschaftsserver der Universität des Saarlandes

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