TRAF1 is a substrate of caspases activated during tumor necrosis factor receptor-alpha-induced apoptosis

J Biol Chem. 2001 Mar 16;276(11):8087-93. doi: 10.1074/jbc.M009450200. Epub 2000 Nov 29.

Abstract

TRAF family proteins are signal-transducing adapter proteins that interact with the cytosolic domains of tumor necrosis factor (TNF) family receptors. Here we show that TRAF1 (but not TRAF2-6) is cleaved by certain caspases in vitro and during TNF-alpha- and Fas-induced apoptosis in vivo. (160)LEVD(163) was identified as the caspase cleavage site within TRAF1, generating two distinct fragments. Significant enhancement of TNF receptor-1 (CD120a)- and, to a lesser extent, Fas (CD95)-mediated apoptosis was observed when overexpressing the C-terminal TRAF1 fragment in HEK293T and HT1080 cells. The same fragment was capable of potently suppressing TNF receptor-1- and TRAF2-mediated nuclear factor-kappaB activation in reporter gene assays, providing a potential mechanism for the enhancement of TNF-mediated apoptosis. Cell death induced by other death receptor-independent stimuli such as cisplatin, staurosporine, and UV irradiation did not result in cleavage of TRAF1, and overexpression of the C-terminal TRAF1 fragment did not enhance cell death in these cases. TRAF1 cleavage was markedly reduced in cells that contain little procaspase-8 protein, suggesting that this apical protease in the TNF/Fas death receptor pathway is largely responsible. These data identify TRAF1 as a specific target of caspases activated during TNF- and Fas-induced apoptosis and illustrate differences in the repertoire of protease substrates cleaved during activation of different apoptotic pathways.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Apoptosis*
  • Caspases / metabolism*
  • Female
  • Humans
  • Lymphocyte Activation
  • Lymphocytes / metabolism
  • NF-kappa B / metabolism
  • Proteins / metabolism*
  • TNF Receptor-Associated Factor 1
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / physiology*
  • fas Receptor / physiology

Substances

  • NF-kappa B
  • Proteins
  • TNF Receptor-Associated Factor 1
  • Tumor Necrosis Factor-alpha
  • fas Receptor
  • Caspases