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PMID:9765397
| Citation |
Liang, XH, Kleeman, LK, Jiang, HH, Gordon, G, Goldman, JE, Berry, G, Herman, B and Levine, B (1998) Protection against fatal Sindbis virus encephalitis by beclin, a novel Bcl-2-interacting protein. J. Virol. 72:8586-96 |
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| Abstract |
bcl-2, the prototypic cellular antiapoptotic gene, decreases Sindbis virus replication and Sindbis virus-induced apoptosis in mouse brains, resulting in protection against lethal encephalitis. To investigate potential mechanisms by which Bcl-2 protects against central nervous system Sindbis virus infection, we performed a yeast two-hybrid screen to identify Bcl-2-interacting gene products in an adult mouse brain library. We identified a novel 60-kDa coiled-coil protein, Beclin, which we confirmed interacts with Bcl-2 in mammalian cells, using fluorescence resonance energy transfer microscopy. To examine the role of Beclin in Sindbis virus pathogenesis, we constructed recombinant Sindbis virus chimeras that express full-length human Beclin (SIN/beclin), Beclin lacking the putative Bcl-2-binding domain (SIN/beclinDeltaBcl-2BD), or Beclin containing a premature stop codon near the 5' terminus (SIN/beclinstop). The survival of mice infected with SIN/beclin was significantly higher (71%) than the survival of mice infected with SIN/beclinDeltaBcl-2BD (9%) or SIN/beclinstop (7%) (P < 0.001). The brains of mice infected with SIN/beclin had fewer Sindbis virus RNA-positive cells, fewer apoptotic cells, and lower viral titers than the brains of mice infected with SIN/beclinDeltaBcl-2BD or SIN/beclinstop. These findings demonstrate that Beclin is a novel Bcl-2-interacting cellular protein that may play a role in antiviral host defense. |
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| Keywords |
Alphavirus Infections/etiology; Alphavirus Infections/prevention & control; Amino Acid Sequence; Animals; Antiviral Agents/chemistry; Antiviral Agents/genetics; Antiviral Agents/physiology; Apoptosis/genetics; Apoptosis Regulatory Proteins; Chromosomes, Human, Pair 17/genetics; Encephalitis, Viral/etiology; Encephalitis, Viral/prevention & control; Female; Genes, bcl-2; Humans; Male; Membrane Proteins; Mice; Molecular Sequence Data; Mutation; Proteins/chemistry; Proteins/genetics; Proteins/physiology; Proto-Oncogene Proteins c-bcl-2/physiology; RNA, Messenger/genetics; RNA, Messenger/metabolism; Saccharomyces cerevisiae/genetics; Sindbis Virus/drug effects; Sindbis Virus/pathogenicity; Sindbis Virus/physiology; Tissue Distribution; Virulence; Virus Replication |
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Significance
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