Diacylglycerol kinase alpha in X linked lymphoproliferative disease type 1

Suresh Velnati, Sara Centonze, Federico Girivetto, Gianluca Baldanzi

Research output: Contribution to journalReview articlepeer-review

Abstract

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.

Original languageEnglish
Article number5816
JournalInternational Journal of Molecular Sciences
Volume22
Issue number11
DOIs
Publication statusPublished - 1 Jun 2021

Keywords

  • Activation-induced cell death
  • ERK
  • PKC
  • SH2D1A
  • SHP-2
  • SLAM
  • Signal transduction

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