HIV protease-generated Casp8p41, when bound and inactivated by Bcl2, is degraded by the proteasome

Sekar Natesampillai, Nathan W Cummins, Zilin Nie, Rahul Sampath, Jason V. Baker, Keith Henry, Marilia Pinzone, Una O'Doherty, Eric Polley, Gary D. Bren, David J Katzmann, Andrew David Badley

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

HIV protease is known to cause cell death, which is dependent upon cleavage of procaspase 8. HIV protease cleavage of procaspase 8 generates Casp8p41, which directly binds Bak with nanomolar affinity, causing Bak activation and consequent cell death. Casp8p41 can also bind Bcl2 with nanomolar affinity, in which case cell death is averted. Central memory CD4 T cells express high levels of Bcl2, possibly explaining why those cells do not die when they reactivate HIV. Here, we determine that the Casp8p41-Bcl2 complex is polyubiquitinated and degraded by the proteasome. Ixazomib, a proteasome inhibitor in clinical use, blocks this pathway, increasing the abundance of Casp8p41 and causing more cells to die in a Casp8p41- dependent manner.

Original languageEnglish (US)
Article numbere00037-18
JournalJournal of Virology
Volume92
Issue number13
DOIs
StatePublished - Jul 1 2018

Fingerprint

HIV Protease
proteasome endopeptidase complex
Proteasome Endopeptidase Complex
cell death
Cell Death
proteinases
Caspase 8
Proteasome Inhibitors
Cause of Death
T-lymphocytes
HIV
cells
T-Lymphocytes

Keywords

  • Apoptosis
  • HIV
  • Proteasome inhibitor

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Cite this

HIV protease-generated Casp8p41, when bound and inactivated by Bcl2, is degraded by the proteasome. / Natesampillai, Sekar; Cummins, Nathan W; Nie, Zilin; Sampath, Rahul; Baker, Jason V.; Henry, Keith; Pinzone, Marilia; O'Doherty, Una; Polley, Eric; Bren, Gary D.; Katzmann, David J; Badley, Andrew David.

In: Journal of Virology, Vol. 92, No. 13, e00037-18, 01.07.2018.

Research output: Contribution to journalArticle

Natesampillai, Sekar ; Cummins, Nathan W ; Nie, Zilin ; Sampath, Rahul ; Baker, Jason V. ; Henry, Keith ; Pinzone, Marilia ; O'Doherty, Una ; Polley, Eric ; Bren, Gary D. ; Katzmann, David J ; Badley, Andrew David. / HIV protease-generated Casp8p41, when bound and inactivated by Bcl2, is degraded by the proteasome. In: Journal of Virology. 2018 ; Vol. 92, No. 13.
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AU - Sampath, Rahul

AU - Baker, Jason V.

AU - Henry, Keith

AU - Pinzone, Marilia

AU - O'Doherty, Una

AU - Polley, Eric

AU - Bren, Gary D.

AU - Katzmann, David J

AU - Badley, Andrew David

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