Molecular ordering of the Fas-apoptotic pathway: the Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-like cysteine proteases.

  • Srinivasula S
  • Ahmad M
  • Fernandes-Alnemri T
 et al. 
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Abstract

The Fas/APO-1-receptor associated cysteine protease Mch5 (MACH/FLICE) is believed to be the enzyme responsible for activating a protease cascade after Fas-receptor ligation, leading to cell death. The Fas-apoptotic pathway is potently inhibited by the cowpox serpin CrmA, suggesting that Mch5 could be the target of this serpin. Bacterial expression of proMch5 generated a mature enzyme composed of two subunits, which are derived from the pre-cursor proenzyme by processing at Asp-227, Asp-233, Asp-391, and Asp-401. We demonstrate that recombinant Mch5 is able to process/activate all known ICE/Ced-3-like cysteine proteases and is potently inhibited by CrmA. This contrasts with the observation that Mch4, the second FADD-related cysteine protease that is also able to process/activate all known ICE/Ced-3-like cysteine proteases, is poorly inhibited by CrmA. These data suggest that Mch5 is the most upstream protease that receives the activation signal from the Fas-receptor to initiate the apoptotic protease cascade that leads to activation of ICE-like proteases (TX, ICE, and ICE-relIII), Ced-3-like proteases (CPP32, Mch2, Mch3, Mch4, and Mch6), and the ICH-1 protease. On the other hand, Mch4 could be a second upstream protease that is responsible for activation of the same protease cascade in CrmA-insensitive apoptotic pathways.

Author-supplied keywords

  • Antigens, CD95
  • Antigens, CD95: metabolism
  • Apoptosis
  • Caspase 8
  • Caspase 9
  • Caspases
  • Cysteine Endopeptidases
  • Cysteine Endopeptidases: genetics
  • Cysteine Endopeptidases: metabolism
  • Enzyme Activation
  • Escherichia coli
  • Escherichia coli: genetics
  • Escherichia coli: metabolism
  • Gene Expression
  • Humans
  • Serpins
  • Serpins: genetics
  • Serpins: metabolism
  • Signal Transduction
  • Viral Proteins

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Authors

  • S M Srinivasula

  • M Ahmad

  • T Fernandes-Alnemri

  • G Litwack

  • E S Alnemri

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