Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1

Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, the...

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Autores principales: Velnati, Suresh, Centonze, Sara, Girivetto, Federico, Baldanzi, Gianluca
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198409/
https://www.ncbi.nlm.nih.gov/pubmed/34072296
http://dx.doi.org/10.3390/ijms22115816
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author Velnati, Suresh
Centonze, Sara
Girivetto, Federico
Baldanzi, Gianluca
author_facet Velnati, Suresh
Centonze, Sara
Girivetto, Federico
Baldanzi, Gianluca
author_sort Velnati, Suresh
collection PubMed
description Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8(+) cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8(+) expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach.
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spelling pubmed-81984092021-06-14 Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1 Velnati, Suresh Centonze, Sara Girivetto, Federico Baldanzi, Gianluca Int J Mol Sci Review Diacylglycerol kinases are intracellular enzymes that control the balance between the secondary messengers diacylglycerol and phosphatidic acid. DGKα and DGKζ are the prominent isoforms that restrain the intensity of T cell receptor signalling by metabolizing PLCγ generated diacylglycerol. Thus, their activity must be tightly controlled to grant cellular homeostasis and refine immune responses. DGKα is specifically inhibited by strong T cell activating signals to allow for full diacylglycerol signalling which mediates T cell response. In X-linked lymphoproliferative disease 1, deficiency of the adaptor protein SAP results in altered T cell receptor signalling, due in part to persistent DGKα activity. This activity constrains diacylglycerol levels, attenuating downstream pathways such as PKCθ and Ras/MAPK and decreasing T cell restimulation induced cell death. This is a form of apoptosis triggered by prolonged T cell activation that is indeed defective in CD8(+) cells of X-linked lymphoproliferative disease type 1 patients. Accordingly, inhibition or downregulation of DGKα activity restores in vitro a correct diacylglycerol dependent signal transduction, cytokines production and restimulation induced apoptosis. In animal disease models, DGKα inhibitors limit CD8(+) expansion and immune-mediated tissue damage, suggesting the possibility of using inhibitors of diacylglycerol kinase as a new therapeutic approach. MDPI 2021-05-29 /pmc/articles/PMC8198409/ /pubmed/34072296 http://dx.doi.org/10.3390/ijms22115816 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Velnati, Suresh
Centonze, Sara
Girivetto, Federico
Baldanzi, Gianluca
Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
title Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
title_full Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
title_fullStr Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
title_full_unstemmed Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
title_short Diacylglycerol Kinase alpha in X Linked Lymphoproliferative Disease Type 1
title_sort diacylglycerol kinase alpha in x linked lymphoproliferative disease type 1
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198409/
https://www.ncbi.nlm.nih.gov/pubmed/34072296
http://dx.doi.org/10.3390/ijms22115816
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