@article{1c420f879e9840298b68e616711b538c,
title = "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.",
keywords = "Apoptosis, HIV, Proteasome inhibitor",
author = "Sekar Natesampillai and Cummins, {Nathan W.} and Zilin Nie and Rahul Sampath and Baker, {Jason V.} and Keith Henry and Marilia Pinzone and Una O'Doherty and Polley, {Eric C.} and Bren, {Gary D.} and Katzmann, {David J.} and Badley, {Andrew D.}",
note = "Funding Information: We thank the study participants who volunteered to provide blood samples for analysis. This study was supported by funding from the National Institute of Allergy and Infectious Diseases (grants R01 AI110173 and R01 AI120698 to A.D.B. and R01-AI-120011 and UM1-AI-126617 to U.O.) and by CTSA grant number UL1 TR000135 (N.W.C.) from the National Center for Advancing Translational Sciences (NCATS), components of the National Institutes of Health (NIH). The contents are solely our responsibility and do not necessarily represent the official view of the NIH. Keith Henry has conducted clinical research for Merck, Janssen, ViiV/GSK, and Gilead (payments were made to the institution-Hennepin County Medical Center). S.N., N.W.C., G.D.B., Z.N., U.O., D.J.K., and A.D.B. conceived and designed the experiments. S.N., N.W.C., G.D.B., Z.N., M.P., U.O., E.C.P., J.V.B., K.H., and R.S. performed the experiments and analyzed data. N.W.C., J.V.B., K.H., and R.S. recruited study participants. S.N., N.W.C., and A.D.B. wrote the manuscript. Funding Information: This study was supported by funding from the National Institute of Allergy and Infectious Diseases (grants R01 AI110173 and R01 AI120698 to A.D.B. and R01-AI-120011 and UM1-AI-126617 to U.O.) and by CTSA grant number UL1 TR000135 (N.W.C.) from the National Center for Advancing Translational Sciences (NCATS), components of the National Institutes of Health (NIH). The contents are solely our responsibility and do not necessarily represent the official view of the NIH. Publisher Copyright: {\textcopyright} 2018 American Society for Microbiology.",
year = "2018",
month = jul,
day = "1",
doi = "10.1128/JVI.00037-18",
language = "English (US)",
volume = "92",
journal = "Journal of virology",
issn = "0022-538X",
publisher = "American Society for Microbiology",
number = "13",
}