The hepatitis C virus core protein contains a BH3 domain that regulates apoptosis through specific interaction with human Mcl-1.
ABSTRACT The hepatitis C virus (HCV) core protein is known to modulate apoptosis and contribute to viral replication and pathogenesis. In this study, we have identified a Bcl-2 homology 3 (BH3) domain in the core protein that is essential for its proapoptotic property. Coimmunoprecipitation experiments showed that the core protein interacts specifically with the human myeloid cell factor 1 (Mcl-1), a prosurvival member of the Bcl-2 family, but not with other prosurvival members (Bcl-X(L) and Bcl-w). Moreover, the overexpression of Mcl-1 protects against core-induced apoptosis. By using peptide mimetics, core was found to release cytochrome c from isolated mitochondria when complemented with Bad. Thus, core is a bona fide BH3-only protein having properties similar to those of Noxa, a BH3-only member of the Bcl-2 family that binds preferentially to Mcl-1. There are three critical hydrophobic residues in the BH3 domain of the core protein, and they are essential for the proapoptotic property of the core protein. Furthermore, the genotype 1b core protein is more effective than the genotype 2a core protein in inducing apoptosis due to a single-amino-acid difference at one of these hydrophobic residues (residue 119). Replacing this residue in the J6/JFH-1 infectious clone (genotype 2a) with the corresponding amino acid in the genotype 1b core protein produced a mutant virus, J6/JFH-1(V119L), which induced significantly higher levels of apoptosis in the infected cells than the parental J6/JFH-1 virus. Furthermore, the core protein of J6/JFH-1(V119L), but not that of J6/JFH-1, interacted with Mcl-1 in virus-infected cells. Taken together, the core protein is a novel BH3-only viral homologue that contributes to the induction of apoptosis during HCV infection.
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ABSTRACT: Many viruses have as part of their arsenal the ability to modulate the apoptotic pathways of the host. It is counter-intuitive that such simple organisms would be efficient at regulating this the most crucial pathway within the host, given the relative complexity of the host cells. Yet, viruses have the potential to initiate or stay the onset of programmed cell death through the manipulation of a variety of key apoptotic proteins. It is the intention of this review to provide an overview of viral gene products that are able to promote or inhibit apoptotic death of the host cell and to discuss their mechanisms of action. It is not until recently that the depth at which viruses exploit the apoptotic pathways of their host has been seen. This understanding may provide a great opportunity for future therapeutic ventures.Journal of General Virology 08/2002; 83(Pt 7):1547-64. · 3.36 Impact Factor
Article: Multiple infection, recombination and genome relationships among begomovirus isolates found in cotton and other plants in Pakistan.[show abstract] [hide abstract]
ABSTRACT: Begomoviruses occur in many plant species in Pakistan and are associated with an epidemic of cotton leaf curl disease that has developed since 1985. PCR analysis with primer pairs specific for each of four already sequenced types of DNA-A of cotton leaf curl virus (CLCuV-PK types a, 26, 72b and 804a), or for okra yellow vein mosaic virus (OYVMV), indicated that many individual naturally infected plants of cotton and other malvaceous species contained two or three begomovirus sequences. Similarly, sequence differences among overlapping fragments of begomovirus DNA-A, amplified from individual naturally infected plants, indicated much multiple infection in malvaceous and non-malvaceous species. Some cotton plants contained DNA-A sequences typical of begomoviruses from non-malvaceous species, and some non-malvaceous plants contained sequences typical of CLCuV-PK. Some DNA-A sequences were chimaeric; they each included elements typical of different types of CLCuV-PK, or of different malvaceous and/or non-malvaceous begomoviruses. Often an apparent recombination site occurred at the origin of replication. No complete CLCuV-PK DNA-A sequence was found in malvaceous or non-malvaceous species collected in Pakistan outside the area of the cotton leaf curl epidemic but chimaeric sequences, including a part that was typical of CLCuV-PK DNA-A, did occur there. We suggest that recombination among such pre-existing sequences was crucial for the emergence of CLCuV-PK. Recombination, following multiple infection, could also explain the network of relationships among many of the begomoviruses found in the Indian subcontinent, and their evolutionary divergence, as a group, from begomoviruses causing similar diseases in other geographical regions.Journal of General Virology 08/2000; 81(Pt 7):1839-49. · 3.36 Impact Factor
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ABSTRACT: The costs of futile care for the dying are great. Futility can present challenges because of the monetary costs of such care, its negative effects on staff members, and the burden it creates in allocating limited resources. Administrators can work to recognize and form a better understanding of futility and thus develop strategies for decreasing non-beneficial care. The author discusses issues surrounding futile care and offers suggestions for administrators to decrease spending related to the administration of futile care for the dying.JONA The Journal of Nursing Administration 01/1997; 26(12):18-23. · 1.42 Impact Factor