Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death

• Verfasst von: Brenner, Dirk [VerfasserIn]
• Verfasst von: Golks, Alexander [VerfasserIn]
• Verfasst von: Krammer, Peter H. [VerfasserIn]
• Verfasst von: Arnold, Rüdiger [VerfasserIn]
• Titel: Activation or suppression of NFκB by HPK1 determines sensitivity to activation-induced cell death
• Verf.angabe: Dirk Brenner, Alexander Golks, Friedemann Kiefer, Peter H Krammer, Rüdiger Arnold
• E-Jahr: 2005
• Jahr: 8 December 2005
• Umfang: 12 S.
• Teil: volume:24
• Teil: year:2005
• Teil: number:24
• Teil: day:21
• Teil: month:12
• Teil: pages:4279-4290
• Teil: extent:12
• Fussnoten: Gesehen am 04.03.2021
• Titel Quelle: Enthalten in: European Molecular Biology OrganizationThe EMBO journal
• Ort Quelle: Heidelberg : EMBO Press, 1982
• Jahr Quelle: 2005
• Band/Heft Quelle: 24(2005), 24 vom: 21. Dez., Seite 4279-4290
• ISSN Quelle: 1460-2075
• DOI: doi:10.1038/sj.emboj.7600894
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: AICD
• Sach-SW: apoptosis
• Sach-SW: IKK
• Sach-SW: signaling
• Sach-SW: TCR
• K10plus-PPN: 1750426862

Abstract

Restimulation of the T-cell receptor (TCR) in activated T cells induces CD95 (Fas/Apo-1)-mediated activation-induced cell death (AICD). The TCR-proximal mechanisms leading to AICD are elusive. Here we characterize hematopoietic progenitor kinase 1 (HPK1) as a differentially regulated TCR-proximal signaling protein involved in AICD of primary T cells. We show that HPK1 is a functional component of the endogenous I?B kinase (IKK) complex and is crucial for TCR-mediated NF?B activation. While full-length HPK1 enhances IKK? phosphorylation, siRNA-mediated knockdown of HPK1 blunts TCR-mediated NF?B activation and increases cell death. We also demonstrate proteolytic processing of HPK1 into HPK1-C, specifically in AICD-sensitive primary T cells. The cleavage product HPK1-C sequesters the inactive IKK complex and suppresses NF?B upon TCR restimulation by binding to IKKα and IKK?. T cells of HPK1-C transgenic mice are sensitized towards TCR-mediated AICD. Consequently, preventing HPK1-C generation in primary T cells by siRNA-mediated knockdown results in decreased AICD. Thus, these results show a novel mechanism of sensitization of T lymphocytes towards AICD by suppression of NF?B, and propose that HPK1 is a life/death switch in T lymphocytes.