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 David Badley

Research output: Contribution to journalArticle

16 Citations (Scopus)

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 - 2014

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Peptide Hydrolases
HIV
T-Lymphocytes
Caspase 8
Cell Death
Activator Appliances
Mutation
Caspases
Apoptosis
Membranes
Proteins

ASJC Scopus subject areas

  • Cell Biology
  • Medicine(all)

Cite this

Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation. / Sainski, Amy M.; Dai, Haiming; Natesampillai, Sekar; Pang, Yuan-Ping; Bren, Gary D.; Cummins, Nathan W; Correia, Cristina; Meng, X. Wei; Tarara, James E.; Ramirez-Alvarado, Marina; Katzmann, David J; Ochsenbauer, Christina; Kappes, John C.; Kaufmann, Scott H; Badley, Andrew David.

In: Journal of Cell Biology, Vol. 206, No. 7, 2014, p. 867-876.

Research output: Contribution to journalArticle

Sainski, AM, Dai, H, Natesampillai, S, Pang, Y-P, Bren, GD, Cummins, NW, Correia, C, Meng, XW, Tarara, JE, Ramirez-Alvarado, M, Katzmann, DJ, Ochsenbauer, C, Kappes, JC, Kaufmann, SH & Badley, AD 2014, 'Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation', Journal of Cell Biology, vol. 206, no. 7, pp. 867-876. https://doi.org/10.1083/jcb.201405051
Sainski, Amy M. ; Dai, Haiming ; Natesampillai, Sekar ; Pang, Yuan-Ping ; Bren, Gary D. ; Cummins, Nathan W ; Correia, Cristina ; Meng, X. Wei ; Tarara, James E. ; Ramirez-Alvarado, Marina ; Katzmann, David J ; Ochsenbauer, Christina ; Kappes, John C. ; Kaufmann, Scott H ; Badley, Andrew David. / Casp8p41 generated by HIV protease kills CD4 T cells through direct Bak activation. In: Journal of Cell Biology. 2014 ; Vol. 206, No. 7. pp. 867-876.
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