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The Cish SH2 domain is essential for PLC-gamma 1 regulation in TCR stimulated CD8(+) T cells

Authors :
Nicholas P. Restifo
Ana Dios-Esponera
Geoffrey Guittard
Itoro Akpan
Asit Kumar Manna
Douglas C. Palmer
Valarie A. Barr
Lawrence E. Samelson
Centre de Recherche en Cancérologie de Marseille (CRCM)
Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Paoli-Calmettes
Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Aix Marseille Université (AMU)
National Institutes of Health [Bethesda] (NIH)
Intramural Research Program of the National Cancer Institute Center for Cancer Research
Aix Marseille Université (AMU)-Institut Paoli-Calmettes
Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Fédération nationale des Centres de lutte contre le Cancer (FNCLCC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Bidaut, Ghislain
Source :
Scientific Reports, Scientific Reports, Nature Publishing Group, 2018, 8 (5336), ⟨10.1038/s41598-018-23549-2⟩, Scientific Reports, Vol 8, Iss 1, Pp 1-9 (2018), Scientific Reports, 2018, 8 (5336), ⟨10.1038/s41598-018-23549-2⟩
Publication Year :
2018
Publisher :
HAL CCSD, 2018.

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.

Details

Language :
English
ISSN :
20452322
Database :
OpenAIRE
Journal :
Scientific Reports, Scientific Reports, Nature Publishing Group, 2018, 8 (5336), ⟨10.1038/s41598-018-23549-2⟩, Scientific Reports, Vol 8, Iss 1, Pp 1-9 (2018), Scientific Reports, 2018, 8 (5336), ⟨10.1038/s41598-018-23549-2⟩
Accession number :
edsair.doi.dedup.....9a7ad3d3ebf592eb8668b0b796bd265c
Full Text :
https://doi.org/10.1038/s41598-018-23549-2⟩