Proteomics

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Proteome of WT and Usp30KO cytotoxic T lymphocytes


ABSTRACT: Recent work in immunometabolism has emphasised the role of mitochondria in both the innate and adaptive immune system. Mitochondria are important in T cell development and differentiation, but less is known about their role in CD8+ effector T cells (CTLs). We found that CTLs that lack the mitochondrial deubiquitinase USP30 undergo promiscuous mitophagy, destroying most of the cellular mitochondria. Surprisingly, this results in a markedly diminished killing capacity, while motility, signalling and secretion remain intact. This study uses quantitative DIA proteomics to measure the impact of USP30 deficiency on the global proteome of IL-2 maintained, 4.5 h TCR retriggered and 4.5 h TCR retriggered + cycloheximide CTL. Unexpectedly, inhibition of mitochondrial translation, through genetic or pharmacologic methods, was the mechanism by which CTL killing was impaired. Reduced mitochondrial translation triggered attenuated cytosolic translation which precluded replenishment of secreted effector molecules thereby limiting the capacity of CTLs to serially kill multiple targets. Thus, mitochondria emerge as a previously unappreciated homeostatic regulator of protein translation required for serial CTL killing.

INSTRUMENT(S): Q Exactive HF-X

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): T Cell, Cell Culture

SUBMITTER: Julia Marchingo  

LAB HEAD: Gillian M. Griffiths

PROVIDER: PXD021508 | Pride | 2022-06-09

REPOSITORIES: Pride

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Mitochondrial translation is required for sustained killing by cytotoxic T cells.

Lisci Miriam M   Barton Philippa R PR   Randzavola Lyra O LO   Ma Claire Y CY   Marchingo Julia M JM   Cantrell Doreen A DA   Paupe Vincent V   Prudent Julien J   Stinchcombe Jane C JC   Griffiths Gillian M GM  

Science (New York, N.Y.) 20211015 6565


T cell receptor activation of naïve CD8<sup>+</sup> T lymphocytes initiates their maturation into effector cytotoxic T lymphocytes (CTLs), which can kill cancer and virally infected cells. Although CTLs show an increased reliance on glycolysis upon acquisition of effector function, we found an essential requirement for mitochondria in target cell–killing. Acute mitochondrial depletion in USP30 (ubiquitin carboxyl-terminal hydrolase 30)–deficient CTLs markedly diminished killing capacity, althoug  ...[more]

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