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The Cish SH2 domain is essential for PLC-γ1 regulation in TCR stimulated CD8+ T cells.
Guittard, Geoffrey; Dios-Esponera, Ana; Palmer, Douglas C; Akpan, Itoro; Barr, Valarie A; Manna, Asit; Restifo, Nicholas P; Samelson, Lawrence E.
  • Guittard G; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland, 20892-4256, USA. geoffrey.guittard@inserm.fr.
  • Dios-Esponera A; INSERM, U1068, CNRS UMR7258, Aix-Marseille Université UM105, Institut Paoli-Calmettes, Centre de Recherche en Cancérologie de Marseille, 13009, Marseille, France. geoffrey.guittard@inserm.fr.
  • Palmer DC; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland, 20892-4256, USA.
  • Akpan I; Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10/CRC, Room 3W-3840, Bethesda, MD, 20892, USA.
  • Barr VA; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland, 20892-4256, USA.
  • Manna A; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland, 20892-4256, USA.
  • Restifo NP; Laboratory of Cellular and Molecular Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland, 20892-4256, USA.
  • Samelson LE; Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Building 10/CRC, Room 3W-3840, Bethesda, MD, 20892, USA.
Sci Rep ; 8(1): 5336, 2018 03 28.
Article en En | MEDLINE | ID: mdl-29593227
ABSTRACT
Cish, participates within a multi-molecular E3 ubiquitin ligase complex, which ubiquitinates target proteins. It has an inhibitory effect on T cell activation mediated by PLC-γ1 regulation, and it functions as a potent checkpoint in CD8+ T cell tumor immunotherapy. To study the structural and functional relationships between Cish and PLC-γ1 during CD8+ T cell activation, we tested mutants of the Cish-SH2 (R107K) and D/BC (L222Q, C226Q) domains. We confirmed that Cish-SH2-specific binding was essential for PLC-γ1 ubiquitination and degradation. This domain was essential for the Cish-mediated inhibition of Ca2+ release upon TCR stimulation. No effect on inhibition of cytokine release was observed with SH2 or D/BC mutants, although the absence of Cish led to an increased release of IFN-γ and TNF-α. Using imaging we showed that Cish was expressed mostly in the cytoplasm and we did not see any Cish clustering at the plasma membrane upon stimulation. We conclude that the Cish-SH2 domain is essential for PLC-γ1 regulation in TCR-stimulated CD8+ T cells.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Antígenos de Linfocitos T / Linfocitos T CD8-positivos / Dominios Homologos src / Fosfolipasa C gamma / Proteínas Supresoras de la Señalización de Citocinas Límite: Animals / Humans Idioma: En Año: 2018 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Receptores de Antígenos de Linfocitos T / Linfocitos T CD8-positivos / Dominios Homologos src / Fosfolipasa C gamma / Proteínas Supresoras de la Señalización de Citocinas Límite: Animals / Humans Idioma: En Año: 2018 Tipo del documento: Article