Viral modulators of cell death provide new links to old pathways

Department of Molecular Microbiology and Immunology, Johns Hopkins University, Baltimore, Maryland, United States
Current Opinion in Cell Biology (Impact Factor: 8.47). 01/2004; 15(6):700-5. DOI: 10.1016/
Source: PubMed


By observing how viruses facilitate their parasitic relationships with host cells, we gain insights into key regulatory pathways of the cell. Not only are mitochondria key players in the regulation of programmed cell death, but many viral regulators of cell death also alter mitochondrial functions either directly or indirectly. Although cytomegalovirus vMIA and Epstein-Barr virus BHRF1 seem to have opposite effects on mitochondrial morphology, they both inhibit cell death. Drosophila Reaper, a regulator of developmental cell death, acts on IAP (inhibitor of apoptosis) proteins to activate caspases, but can regulate mitochondrial permeability in vitro. Despite its pivotal role in Drosophila, homologues of Reaper in other species were not previously known. Recently, amino acid sequence similarity was recognized between Drosophila Reaper and a protein known to be important for the replication and virulence of mosquito-borne bunyaviruses that cause human encephalitis. Thus, viral mechanisms for regulating apoptosis are diverse and not fully elucidated but promise to provide new insights.

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Available from: J. Marie Hardwick
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    • " sug - gesting precellular origins for at least some viral genomes . Like the viral oncogenes of avian and other retroviruses that differ from their homo - logs in host cells ( proto - oncogene ) , viral BCL - 2 - like proteins appear to be resistant to cellular regulatory mechanisms relative to their cellular counterparts ( Bellows et al . 2000 ; Irusta et al . 2003 ) ."
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    ABSTRACT: BCL-2 family proteins are the regulators of apoptosis, but also have other functions. This family of interacting partners includes inhibitors and inducers of cell death. Together they regulate and mediate the process by which mitochondria contribute to cell death known as the intrinsic apoptosis pathway. This pathway is required for normal embryonic development and for preventing cancer. However, before apoptosis is induced, BCL-2 proteins have critical roles in normal cell physiology related to neuronal activity, autophagy, calcium handling, mitochondrial dynamics and energetics, and other processes of normal healthy cells. The relative importance of these physiological functions compared to their apoptosis functions in overall organismal physiology is difficult to decipher. Apoptotic and noncanonical functions of these proteins may be intertwined to link cell growth to cell death. Disentanglement of these functions may require delineation of biochemical activities inherent to the characteristic three-dimensional shape shared by distantly related viral and cellular BCL-2 family members.
    Full-text · Article · Feb 2013 · Cold Spring Harbor perspectives in biology
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    • "Given that the severity of the hepatitis has been associated with the amount and distribution of PCV2 present, and that PCV2 can replicate in hepatocytes and macrophages (Pérez-Martín et al., 2007), it has been suggested that the extent of hepatocyte infection is directly attributable to lesion severity (Rosell et al., 2000; Hirai et al., 2003; Krakowka et al., 2005). A number of viruses encode pro-apoptotic genes, activating their transcription to facilitate the release of viral progeny during acute infection (O'Brien, 1998; Benedict et al., 2003; Irusta et al., 2003). The potential role of virus-induced apoptosis in the pathogenesis of the hepatitis associated with PMWS remains unclear. "
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    ABSTRACT: The degree of apoptosis in the livers of pigs with hepatitis due to naturally-occurring postweaning multisystemic wasting syndrome (PMWS) was evaluated semi-quantitatively by immunohistochemical detection of the apoptotic marker cleaved caspase-3 (CCasp3). The amount and distribution of porcine circovirus type 2 (PCV2) virus in the liver was evaluated using in situ hybridisation. Livers with mild, stage I hepatitis exhibited similar degrees of apoptosis to controls; those with stage II lesions had variable apoptotic rates, ranging from mild to high, and in livers with more severe, stage III hepatitis, high levels of hepatocyte apoptosis was a feature. Statistical analyses indicated a positive association between the rate of apoptosis, the severity of the hepatitis and the amount of PCV2 DNA in the liver. Double immunolabelling for CCasp3 and PCV2 DNA revealed a predominance of cells labelling only for PCV2, followed by fewer cells labelling only for CCasp3, and the least number labelling for both. The findings suggest that apoptosis, possibly triggered by PCV2 infection and/or hepatic inflammation, plays a key role in the pathogenesis of hepatitis in pigs with naturally-occurring PMWS.
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