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Molecular and Cellular Biology, August 2009, p. 4431-4440, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.02261-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

A New C-Terminal Cleavage Product of Procaspase-8, p30, Defines an Alternative Pathway of Procaspase-8 Activation{triangledown} ,{dagger}

Julia C. Hoffmann,# Alexander Pappa,#,{ddagger} Peter H. Krammer, and Inna N. Lavrik*

Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D69120 Heidelberg, Germany

Received 21 December 2007/ Returned for modification 26 March 2008/ Accepted 9 June 2009

Caspase-8 is the main initiator caspase in death receptor-induced apoptosis. Procaspase-8 is activated at the death-inducing signaling complex (DISC). Previous studies suggested a two-step model of procaspase-8 activation. The first cleavage step occurs between the protease domains p18 and p10. The second cleavage step takes place between the prodomain and the large protease subunit (p18). Subsequently, the active caspase-8 heterotetramer p182-p102 is released into the cytosol, starting the apoptotic signaling cascade. In this report, we have further analyzed procaspase-8 processing upon death receptor stimulation directly at the DISC and in the cytosol. We have found an alternative sequence of cleavage events for procaspase-8. We have demonstrated that the first cleavage can also occur between the prodomain and the large protease subunit (p18). The resulting cleavage product, p30, contains both the large protease subunit (p18) and the small protease subunit (p10). p30 is further processed to p10 and p18 by active caspases. Furthermore, we show that p30 can sensitize cells toward death receptor-induced apoptosis. Taken together, our data suggest an alternative mechanism of procaspase-8 activation at the DISC.

* Corresponding author. Mailing address: Division of Immunogenetics, Tumorimmunology Program, German Cancer Research Center, Im Neuenheimer Feld 280, D69120 Heidelberg, Germany. Phone: 49-6221-423774. Fax: 49-6221-411715. E-mail: i.lavrik{at}dkfz.de

{triangledown} Published ahead of print on 15 June 2009.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

# Equal contribution.

{ddagger} Present address: Global Medical Science, Stryker Osteosynthesis, Boetzinger Strasse 41, D-79111 Freiburg, Germany.

Molecular and Cellular Biology, August 2009, p. 4431-4440, Vol. 29, No. 16
0270-7306/09/$08.00+0     doi:10.1128/MCB.02261-07
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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