ORIGINAL ARTICLE

Cell Research (2008): 961-973
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HIV-1 Vpr-induced cell death in Schizosaccharomyces pombe is reminiscent of apoptosis

Sylvain Huard^1,§, Mingzhong Chen², Kristen E Burdette³, Csaba Fenyvuesvolgyi¹, Min Yu², Robert T Elder² and Richard Y Zhao^1,2,3,4

Correspondence: Richard Y Zhao Tel: +1-410-706-6301; Fax: +1-410-706-6303 E-mail: rzhao@som.umaryland.edu §Current address: Department of Molecular and Cellular Pharmacology, University of Miami, Miami, FL, USA

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Human immunodeficiency virus type 1 (HIV-1) Vpr induces cell death in mammalian and fission yeast cells, suggesting that Vpr may affect a conserved cellular process. It is unclear, however, whether Vpr-induced yeast cell death mimics Vpr-mediated apoptosis in mammalian cells. We have recently identified a number of Vpr suppressors that not only suppress Vpr-induced cell death in fission yeast, but also block Vpr-induced apoptosis in mammalian cells. These findings suggest that Vpr-induced cell death in yeast may resemble some of the apoptotic processes of mammalian cells. The goal of this study was to develop and validate a fission yeast model system for future studies of apoptosis. Similar to Vpr-induced apoptosis in mammalian cells, we show here that Vpr in fission yeast promotes phosphatidylserine externalization and induces hyperpolarization of mitochondria, leading to changes of mitochondrial membrane potential. Moreover, Vpr triggers production of reactive oxygen species (ROS), indicating that the apoptotic-like cell death might be mediated by ROS. Interestingly, Vpr induces unique morphologic changes in mitochondria that may provide a simple marker for measuring the apoptotic-like process in fission yeast. To verify this possibility, we tested two Vpr suppressors (EF2 and Hsp16) that suppress Vpr-induced apoptosis in mammalian cells in addition to a newly identified Vpr suppressor (Skp1). All three proteins abolished cell death mediated by Vpr and restored normal mitochondrial morphology in the yeast cells. In conclusion, Vpr-induced cell death in fission yeast resembles the mammalian apoptotic process. Fission yeast may thus potentially be used as a simple model organism for the future study of the apoptotic-like process induced by Vpr and other proapoptotic agents.

Cell Research (2008) 18:961–973. doi: 10.1038/cr.2008.272; published online 12 August 2008

Keywords: fission yeast (Schizosaccharomyces pombe), HIV-1 Vpr, apoptosis, mitochondria, model organism