HIV Protease-Generated Casp8p41, When Bound and Inactivated by Bcl2, Is Degraded by the Proteasome.

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.IMPORTANCE The Casp8p41 pathway of cell death is unique to HIV-infected cells yet is blocked by Bcl2. Once bound by Bcl2, Casp8p41 is polyubiquitinated and degraded by the proteasome. Proteasome inhibition blocks degradation of Casp8p41, increasing Casp8p41 levels and causing more HIV-infected cells to die.

journal_name

J Virol

journal_title

Journal of virology

authors

Natesampillai S,Cummins NW,Nie Z,Sampath R,Baker JV,Henry K,Pinzone M,O'Doherty U,Polley EC,Bren GD,Katzmann DJ,Badley AD

doi

10.1128/JVI.00037-18

subject

Has Abstract

pub_date

2018-06-13 00:00:00

issue

13

eissn

0022-538X

issn

1098-5514

pii

JVI.00037-18

journal_volume

92

pub_type

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