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Journal of Virology, November 1998, p. 8586-8596, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Protection against Fatal Sindbis Virus Encephalitis by Beclin, a Novel Bcl-2-Interacting Protein

Xiao Huan Liang,1 Linda K. Kleeman,1 Hui Hui Jiang, Gerald Gordon,2 James E. Goldman,3 Gail Berry,2 Brian Herman,2,dagger and Beth Levine1,*

Departments of Medicine1 and Pathology,3 Columbia University College of Physicians and Surgeons, New York, New York 10032, and Department of Cell Biology and Anatomy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 275992

Received 5 May 1998/Accepted 6 July 1998

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/beclinDelta Bcl-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/beclinDelta Bcl-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/beclinDelta Bcl-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.

* Corresponding author. Mailing address: Department of Medicine, Columbia University College of Physicians and Surgeons, 630 W. 168th St. P & S 8-444, New York, NY 10032. Phone: (212) 305-7312. Fax: (212) 305-7290. E-mail: Levine{at}cuccfa.ccc.columbia.edu.

dagger Present address: Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX 78284.

Journal of Virology, November 1998, p. 8586-8596, Vol. 72, No. 11
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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