HIV-1 protease-induced apoptosis

0429635 - ÚOCHB 2015 RIV GB eng J - Článek v odborném periodiku
Rumlová, Michaela - Křížová, Ivana - Keprová, Alena - Hadravová, Romana - Doležal, Michal - Strohalmová, Karolína - Pichová, Iva - Hájek, Miroslav - Ruml, T.
HIV-1 protease-induced apoptosis.
Retrovirology. Roč. 11, May 20 (2014), 37/1-37/15. E-ISSN 1742-4690
Grant CEP: GA ČR GA204/09/1388
Institucionální podpora: RVO:61388963
Klíčová slova: HIV protease * BCA3 * AKIP-1 * apoptosis * mitochondria
Kód oboru RIV: EE - Mikrobiologie, virologie
Impakt faktor: 4.185, rok: 2014
http://www.retrovirology.com/content/11/1/37

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 AI Gamma 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.
Trvalý link: http://hdl.handle.net/11104/0234752