Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)867-876
Number of pages10
JournalJournal of Cell Biology
Volume206
Issue number7
DOIs
StatePublished - Jan 1 2014

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ASJC Scopus subject areas

  • Cell Biology

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