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J. Biol. Chem., Vol. 282, Issue 29, 21124-21133, July 20, 2007

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The Hepatitis E Virus Orf3 Protein Protects Cells from Mitochondrial Depolarization and Death^*

From the Virology Group, International Centre for Genetic Engineering and Biotechnology, New Delhi 110 067, India

The biology and pathogenesis of hepatitis E virus are poorly understood due to the lack of an in vitro culture or infection models. The viral Orf3 protein activates the cellular mitogen-activated protein kinase pathway and is likely to modulate the host cell environment for efficient viral replication. We screened for cellular genes whose transcription was differentially up-regulated in an Orf3-expressing stable cell line (ORF3/4). The gene for mitochondrial voltage-dependent anion channel (VDAC) was one such candidate. The up-regulation of VDAC in ORF3/4 cells was confirmed by Northern and Western blotting in various cell lines. Transfection of ORF3/4 cells with an ORF3-specific small interfering RNA led to a reduction in VDAC protein levels. VDAC is a critical mitochondrial outer membrane protein, and its overexpression results in apoptosis. Surprisingly, Orf3-expressing cells were protected against staurosporine-induced cell death by preservation of mitochondrial potential and membrane integrity. A small interfering RNA-mediated reduction in Orf3 and VDAC levels also made cells sensitive to staurosporine. Chemical cross-linking showed Orf3-expressing cells to contain higher levels of oligomeric VDAC. These cells also contained higher levels of hexokinase I that directly interacted with VDAC. This interaction is known to preserve mitochondrial potential and prevent cytochrome c release. We report here the first instance of a viral protein promoting cell survival through such a mechanism.

Received for publication, February 27, 2007 , and in revised form, April 26, 2007.

^* This work was supported by an International Senior Research Fellowship in Biomedical Sciences of the Wellcome Trust (to S. J.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Recipient of a Senior Research Fellowship of CSIR, India.

² Present address: Al-Ain University, Biochemistry, FMHS, UAEU, Al-Ain 17666, United Arab Emirates.

³ To whom correspondence should be addressed. Tel.: 91-11-26177357 (ext. 253); Fax: 91-11-26162316; E-mail: shahid{at}icgeb.res.in.

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