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HIV-1 protease-induced apoptosis
M. Rumlová, I. Křížová, A. Keprová, R. Hadravová, M. Doležal, K. Strohalmová, I. Pichová, M. Hájek, T. Ruml,
Jazyk angličtina Země Anglie, Velká Británie
Typ dokumentu časopisecké články, práce podpořená grantem
BioMedCentral Open Access od 2004
Directory of Open Access Journals od 2004
Free Medical Journals od 2004
PubMed Central od 2004
Europe PubMed Central od 2004
ProQuest Central od 2009-01-01
Open Access Digital Library od 2004-02-01
Open Access Digital Library od 2004-01-01
Open Access Digital Library od 2004-01-01
Medline Complete (EBSCOhost) od 2004-02-27
Health & Medicine (ProQuest) od 2009-01-01
ROAD: Directory of Open Access Scholarly Resources od 2004
Springer Journals Complete - Open Access od 2004-12-01
Springer Nature OA/Free Journals od 2004-12-01
Odkazy
PubMed
24886575
DOI
10.1186/1742-4690-11-37
Knihovny.cz E-zdroje
- MeSH
- adaptorové proteiny signální transdukční genetika metabolismus MeSH
- apoptóza genetika MeSH
- buněčné linie MeSH
- CD4-pozitivní T-lymfocyty metabolismus MeSH
- fragmentace DNA MeSH
- HEK293 buňky MeSH
- HeLa buňky MeSH
- HIV infekce genetika metabolismus MeSH
- HIV-1 genetika metabolismus MeSH
- HIV-proteasa genetika metabolismus MeSH
- jaderné proteiny genetika metabolismus MeSH
- lidé MeSH
- mitochondriální proteiny genetika metabolismus MeSH
- mitochondrie genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- promotorové oblasti (genetika) genetika MeSH
- protein X asociovaný s bcl-2 genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: Apoptosis is one of the presumptive causes of CD4+ T cell depletion during HIV infection and progression to AIDS. However, the precise role of HIV-1 in this process remains unexplained. HIV-1 protease (PR) has been suggested as a possible factor, but a direct link between HIV-1 PR enzymatic activity and apoptosis has not been established. RESULTS: Here, we show that expression of active HIV-1 PR induces death in HeLa and HEK-293 cells via the mitochondrial apoptotic pathway. This conclusion is based on in vivo observations of the direct localization of HIV-1 PR in mitochondria, a key player in triggering apoptosis. Moreover, we observed an HIV-1 PR concentration-dependent decrease in mitochondrial membrane potential and the role of HIV-1 PR in activation of caspase 9, PARP cleavage and DNA fragmentation. In addition, in vitro data demonstrated that HIV-1 PR mediates cleavage of mitochondrial proteins Tom22, VDAC and ANT, leading to release of AIF and Hsp60 proteins. By using yeast two-hybrid screening, we also identified a new HIV-1 PR interaction partner, breast carcinoma-associated protein 3 (BCA3). We found that BCA3 accelerates p53 transcriptional activity on the bax promoter, thus elevating the cellular level of pro-apoptotic Bax protein. CONCLUSION: In summary, our results describe the involvement of HIV-1 PR in apoptosis, which is caused either by a direct effect of HIV-1 PR on mitochondrial membrane integrity or by its interaction with cellular protein BCA3.
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- $a Rumlová, Michaela $u Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v,v,i,, IOCB & Gilead Research Center, Flemingovo nám, 2, 166 10 Prague, Czech Republic. rumlova@uochb.cas.cz.
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- $a BACKGROUND: Apoptosis is one of the presumptive causes of CD4+ T cell depletion during HIV infection and progression to AIDS. However, the precise role of HIV-1 in this process remains unexplained. HIV-1 protease (PR) has been suggested as a possible factor, but a direct link between HIV-1 PR enzymatic activity and apoptosis has not been established. RESULTS: Here, we show that expression of active HIV-1 PR induces death in HeLa and HEK-293 cells via the mitochondrial apoptotic pathway. This conclusion is based on in vivo observations of the direct localization of HIV-1 PR in mitochondria, a key player in triggering apoptosis. Moreover, we observed an HIV-1 PR concentration-dependent decrease in mitochondrial membrane potential and the role of HIV-1 PR in activation of caspase 9, PARP cleavage and DNA fragmentation. In addition, in vitro data demonstrated that HIV-1 PR mediates cleavage of mitochondrial proteins Tom22, VDAC and ANT, leading to release of AIF and Hsp60 proteins. By using yeast two-hybrid screening, we also identified a new HIV-1 PR interaction partner, breast carcinoma-associated protein 3 (BCA3). We found that BCA3 accelerates p53 transcriptional activity on the bax promoter, thus elevating the cellular level of pro-apoptotic Bax protein. CONCLUSION: In summary, our results describe the involvement of HIV-1 PR in apoptosis, which is caused either by a direct effect of HIV-1 PR on mitochondrial membrane integrity or by its interaction with cellular protein BCA3.
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