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

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          Abstract

          HIV protease converts procaspase 8 into Casp8p41, which binds and activates Bak to induce cell death in infected CD4 T cells.

          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.

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          Molecular dynamics with coupling to an external bath

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            AMBER, a package of computer programs for applying molecular mechanics, normal mode analysis, molecular dynamics and free energy calculations to simulate the structural and energetic properties of molecules

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              BH3 domains of BH3-only proteins differentially regulate Bax-mediated mitochondrial membrane permeabilization both directly and indirectly.

              Using a Bax-dependent membrane-permeabilization assay, we show that peptides corresponding to the BH3 domains of Bcl-2 family "BH3-only" proteins have dual functions. Several BH3 peptides relieved the inhibition of Bax caused by the antiapoptotic Bcl-x(L) and/or Mcl-1 proteins, some displaying a specificity for either Bcl-x(L) or Mcl-1. Besides having this derepression function, the Bid and Bim peptides activated Bax directly and were the only BH3 peptides tested that could potently induce cytochrome c release from mitochondria in cultured cells. Furthermore, Bax activator molecules (cleaved Bid protein and the Bim BH3 peptide) synergistically induced cytochrome c release when introduced into cells along with derepressor BH3 peptides. These observations support a unified model of BH3 domain function, encompassing both positive and negative regulation of other Bcl-2 family members. In this model, the simple inhibition of antiapoptotic functions is insufficient to induce apoptosis unless a direct activator of Bax or Bak is present.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                29 September 2014
                : 206
                : 7
                : 867-876
                Affiliations
                [1 ]Department of Molecular Pharmacology and Experiment Therapeutics , [2 ]Division of Oncology Research , [3 ]Division of Infectious Diseases , and [4 ]Department of Medicine, University of Alabama, Birmingham, AL 35294
                [5 ]Department of Biochemistry and Molecular Biology and [6 ]Department of Molecular Medicine, Mayo Clinic, Rochester MN 55905
                Author notes
                Correspondence to Scott H. Kaufmann: Kaufmann.Scott@ 123456Mayo.edu ; or Andrew D. Badley: Badley.Andrew@ 123456Mayo.edu

                A.M. Sainski, H. Dai, and S. Natesampillai contributed equally to this paper.

                Article
                201405051
                10.1083/jcb.201405051
                4178959
                25246614
                d081cb6c-a61c-4785-a1a8-ee34497752b4
                © 2014 Sainski et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

                History
                : 14 May 2014
                : 14 August 2014
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                Cell biology
                Cell biology

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