TY - JOUR
T1 - Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation
AU - Sainski, Amy M.
AU - Dai, Haiming
AU - Natesampillai, Sekar
AU - Pang, Yuan Ping
AU - Bren, Gary D.
AU - Cummins, Nathan W.
AU - Correia, Cristina
AU - Meng, X. Wei
AU - Tarara, James E.
AU - Ramirez-Alvarado, Marina
AU - Katzmann, David J.
AU - Ochsenbauer, Christina
AU - Kappes, John C.
AU - Kaufmann, Scott H.
AU - Badley, Andrew D.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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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U2 - 10.1083/jcb.201405051
DO - 10.1083/jcb.201405051
M3 - Article
C2 - 25246614
AN - SCOPUS:84907758778
SN - 0021-9525
VL - 206
SP - 867
EP - 876
JO - Journal of Cell Biology
JF - Journal of Cell Biology
IS - 7
ER -