DOI: 10.1073/pnas.93.25.14486. 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

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

10.1073/pnas.93.25.14486

Crossref journal-article

Proceedings of the National Academy of Sciences

Proceedings of the National Academy of Sciences (341)

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 precursor 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.

Bibliography

Srinivasula, S. M., Ahmad, M., Fernandes-Alnemri, T., Litwack, G., & Alnemri, E. S. (1996). Molecular ordering of the Fas-apoptotic pathway: The Fas/APO-1 protease Mch5 is a CrmA-inhibitable protease that activates multiple Ced-3/ICE-likeâcysteineâproteases. Proceedings of the National Academy of Sciences, 93(25), 14486â14491.

Authors 5

Srinivasa M. Srinivasula (first)
Manzoor Ahmad (additional)
Teresa Fernandes-Alnemri (additional)
Gerald Litwack (additional)
Emad S. Alnemri (additional)

References 24 Referenced 408

10.1016/0092-8674(95)90422-0
10.1016/S1074-7613(00)80428-8
10.1016/0955-0674(95)80088-3
Alnemri E. S. (1996) J. Cell. Biochem. in press.
10.1073/pnas.93.15.7464
10.1074/jbc.271.43.27099
10.1016/S0092-8674(00)81265-9
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T Fernandes-Alnemri, A Takahashi, R Armstrong, J Krebs, L Fritz, K J Tomaselli, L Wang, Z Yu, C M Croce, W C Earnshaw, G Litwack, E S Alnemri Cancer Res 55, 6045–6052 (1995). / Cancer Res by Fernandes-Alnemri T (1995)
T Fernandes-Alnemri, G Litwack, E S Alnemri Cancer Res 55, 2737–2742 (1995). / Cancer Res by Fernandes-Alnemri T (1995)
10.1074/jbc.270.16.9378
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10.1126/science.8303301
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10.1046/j.1365-2443.1996.00255.x

Dates

Type	When
Created	23 years, 1 month ago (July 26, 2002, 10:34 a.m.)
Deposited	3 years, 4 months ago (April 13, 2022, 2:29 p.m.)
Indexed	1 month ago (July 25, 2025, 6:32 a.m.)
Issued	28 years, 8 months ago (Dec. 10, 1996)
Published	28 years, 8 months ago (Dec. 10, 1996)
Published Online	28 years, 8 months ago (Dec. 10, 1996)
Published Print	28 years, 8 months ago (Dec. 10, 1996)

Funders 0

None

BibTeX

@article{Srinivasula_1996, title={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}, volume={93}, ISSN={1091-6490}, url={http://dx.doi.org/10.1073/pnas.93.25.14486}, DOI={10.1073/pnas.93.25.14486}, number={25}, journal={Proceedings of the National Academy of Sciences}, publisher={Proceedings of the National Academy of Sciences}, author={Srinivasula, Srinivasa M. and Ahmad, Manzoor and Fernandes-Alnemri, Teresa and Litwack, Gerald and Alnemri, Emad S.}, year={1996}, month=dec, pages={14486–14491} }

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