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

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.

[1]  M. Peter,et al.  The CD95(APO-1/Fas) DISC and beyond , 2003, Cell Death and Differentiation.

[2]  Xiaolu Yang,et al.  c‐FLIPL is a dual function regulator for caspase‐8 activation and CD95‐mediated apoptosis , 2002, The EMBO journal.

[3]  M. Prevost,et al.  Bcl-2 and Bax modulate adenine nucleotide translocase activity. , 2003, Cancer research.

[4]  B. Korant,et al.  Apoptosis mediated by HIV protease is preceded by cleavage of Bcl-2. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[5]  G. Kroemer,et al.  Inhibition of adenine nucleotide translocator pore function and protection against apoptosis in vivo by an HIV protease inhibitor. , 2005, The Journal of clinical investigation.

[6]  R. Haworth,et al.  Relationship between configuration, function, and permeability in calcium-treated mitochondria. , 1976, The Journal of biological chemistry.

[7]  R. Shoeman,et al.  Cleavage of human and mouse cytoskeletal and sarcomeric proteins by human immunodeficiency virus type 1 protease. Actin, desmin, myosin, and tropomyosin. , 1993, The American journal of pathology.

[8]  B. Moss,et al.  HIV-1 protease cleaves actin during acute infection of human T-lymphocytes. , 1992, AIDS research and human retroviruses.

[9]  Lorenzo Galluzzi,et al.  Mitochondrial membrane permeabilization in cell death. , 2007, Physiological reviews.

[10]  R. Sékaly,et al.  HIV-1 protease processes procaspase 8 to cause mitochondrial release of cytochrome c, caspase cleavage and nuclear fragmentation , 2002, Cell Death and Differentiation.

[11]  J. Houghton,et al.  Shared pathways: Death receptors and cytotoxic drugs in cancer therapy , 2009, Pathology Oncology Research.

[12]  Daniel C. Douek,et al.  Human Immunodeficiency Virus Type 1 Protease Cleaves Procaspase 8 In Vivo , 2007, Journal of Virology.

[13]  M. Peter,et al.  Cleavage of FLICE (caspase‐8) by granzyme B during cytotoxic T lymphocyte‐induced apoptosis , 1997, European journal of immunology.

[14]  J. Tschopp,et al.  The Long Form of FLIP Is an Activator of Caspase-8 at the Fas Death-inducing Signaling Complex* , 2002, The Journal of Biological Chemistry.

[15]  A. Halestrap,et al.  Cyclosporin A binding in mitochondrial cyclophilin inhibits the permeability transition pore and protects hearts from ischaemia/reperfusion injury , 2004, Molecular and Cellular Biochemistry.

[16]  Luis Carrasco,et al.  HIV-1 protease cleaves eukaryotic initiation factor 4G and inhibits cap-dependent translation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  M. Lutter,et al.  tBid interaction with cardiolipin primarily orchestrates mitochondrial dysfunctions and subsequently activates Bax and Bak , 2005, Cell Death and Differentiation.