Analysis of HIV Protease Killing Through Caspase 8 Reveals a Novel Interaction Between Caspase 8 and Mitochondria



Alicia Algeciras-Schimnich1, Anne-Sophie Belzacq-Casagrande3, Gary D Bren1, Zilin Nie1, Julie A Taylor1, Stacey A Rizza1, Catherine Brenner3, Andrew D Badley*, 1, 2
1 Division of Infectious Diseases, Mayo Clinic, Rochester, MN 55905, USA
2 Program in Translational Immunovirology and Biodefense, Mayo Clinic, Rochester, MN 55905, USA
3 University of Versailles St-Quentin, UMR CNRS 8159, LGBC, 45 avenue des Etats-Unis, Versailles, France


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2007 Bentham Science Publishers Ltd.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.5/), which permits unrestrictive use, distribution, and reproduction in any medium, provided the original work is properly cited.

* Address correspondence to this author at the Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA; Tel: 507-266-5065; Fax: 507-284-3757; E-mail: badley.andrew@mayo.edu


Abstract

Human Immunodeficiency Virus (HIV) protease initiates apoptosis of HIV-infected cells by proteolytic cleavage of procaspase 8, creating a novel peptide termed casp8p41. Expression of casp8p41 alone is sufficient to initiate caspase-dependent cell death associated with mitochondrial depolarization. Since casp8p41 does not contain the catalytic cysteine at position 360, the mechanism by which casp8p41 initiates apoptosis is unclear. We demonstrate that casp8p41 directly causes mitochondrial depolarization and release of cytochrome c with downstream caspase 9 activation. Moreover, death induced by casp8p41 requires the presence of mitochondria, and in intact cells, casp8p41 colocalizes with mitochondria. These results illuminate a novel mechanism of cell death induced by a caspase 8 cleavage fragment whereby mitochondrial interaction leads to depolarization and cytochrome c release.