Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation |
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| Authors: | Amy M Sainski Haiming Dai Sekar Natesampillai Yuan-Ping Pang Gary D Bren Nathan W Cummins Cristina Correia X Wei Meng James E Tarara Marina Ramirez-Alvarado David J Katzmann Christina Ochsenbauer John C Kappes Scott H Kaufmann Andrew D Badley |
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| Institution: | 1.Department of Molecular Pharmacology and Experiment Therapeutics, 2.Division of Oncology Research, 3.Division of Infectious Diseases, and 4.Department of Medicine, University of Alabama, Birmingham, AL 35294;5.Department of Biochemistry and Molecular Biology, and 6.Department of Molecular Medicine, Mayo Clinic, Rochester MN 55905 |
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| Abstract: | Previous studies have shown that human immunodeficiency virus (HIV) protease cleaves procaspase 8 to a fragment, termed Casp8p41, that lacks caspase activity but nonetheless contributes to T cell apoptosis. Herein, we show that Casp8p41 contains a domain that interacts with the BH3-binding groove of pro-apoptotic Bak to cause Bak oligomerization, Bak-mediated membrane permeabilization, and cell death. Levels of active Bak are higher in HIV-infected T cells that express Casp8p41. Conversely, targeted mutations in the Bak-interacting domain diminish Bak binding and Casp8p41-mediated cell death. Similar mutations in procaspase 8 impair the ability of HIV to kill infected T cells. These observations support a novel paradigm in which HIV converts a normal cellular constituent into a direct activator that functions like a BH3-only protein. |
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