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Research article

Cleavage of Notch1 by granzyme B disables its transcriptional activity

Geert van Tetering, Niels Bovenschen, Jan Meeldijk, Paul J. van Diest, Marc Vooijs
Biochemical Journal Jul 15, 2011, 437 (2) 313-322; DOI: 10.1042/BJ20110226
Geert van Tetering
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
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Niels Bovenschen
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
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Jan Meeldijk
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
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Paul J. van Diest
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The Netherlands
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Marc Vooijs
Department of Pathology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, Utrecht, The NetherlandsDepartment of Radiotherapy (MAASTRO)/GROW School for Oncology and Developmental Biology, University of Maastricht, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands
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  • For correspondence: marc.vooijs@maastrichtuniversity.nl
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Abstract

Granzyme-mediated cell death is the main pathway for cytotoxic lymphocytes to kill virus-infected and tumour cells. A major player in this process is GrB (granzyme B), which triggers apoptosis in both caspase-dependent and caspase-independent pathways. A caspase-independent substrate of GrB is the highly conserved transmembrane receptor Notch1. The GrB cleavage sites in Notch1 and functional consequences of Notch1 cleavage by GrB were unknown. In the present study, we confirmed that Notch1 is a direct and caspase-independent substrate of GrB. We demonstrate that GrB cleaved the intracellular Notch1 domain at least twice at two distinct aspartic acids, Asp1860 and Asp1961. GrB cleavage of Notch1 can occur in all subcellular compartments, during maturation of the receptor, at the membrane, and in the nucleus. GrB also displayed perforin-independent functions by cleaving the extracellular domain of Notch1. Overall, cleavage of Notch1 by GrB resulted in a loss of transcriptional activity, independent of Notch1 activation. We conclude that GrB disables Notch1 function, probably resulting in anti-cellular proliferation and cell death signals.

  • cleavage
  • granzyme B
  • Notch signalling
  • proteolysis
  • γ-secretase
  • serine protease

Abbreviations: CSL, CBF1/suppressor of Hairless/Lag-1; CTL, cytotoxic T-lymphocyte; DBZ, dibenzazepine; ER, endoplasmic reticulum; GrB, granzyme B; HA, haemagglutinin; 6MT, 6Myc tag; N1FL, full-length Notch1; NECD, Notch extracellular domain; NICD, Notch intracellular domain; NK, natural killer; PKB, protein kinase B; RBP-Jκ, recombination signal-binding protein 1 for Jκ; RAM, RBP-Jκ-associated molecule; SLO, streptolysin O; TBS, Tris-buffered saline; TMIC, transmembrane and intracellular domain; Z-VAD-FMK, benzyloxycarbonyl-Val-Ala-DL-Asp-fluoromethylketone

  • © The Authors Journal compilation © 2011 Biochemical Society
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July 2011

Volume: 437 Issue: 2

Biochemical Journal: 437 (2)
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Cleavage of Notch1 by granzyme B disables its transcriptional activity
Geert van Tetering, Niels Bovenschen, Jan Meeldijk, Paul J. van Diest, Marc Vooijs
Biochemical Journal Jul 2011, 437 (2) 313-322; DOI: 10.1042/BJ20110226
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Cleavage of Notch1 by granzyme B disables its transcriptional activity
Geert van Tetering, Niels Bovenschen, Jan Meeldijk, Paul J. van Diest, Marc Vooijs
Biochemical Journal Jul 2011, 437 (2) 313-322; DOI: 10.1042/BJ20110226

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Keywords

cleavage
granzyme B
Notch signalling
proteolysis
γ-secretase
serine protease

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