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J. Biol. Chem., Vol. 281, Issue 12, 8135-8142, March 24, 2006

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Enhanced ₁ Microglobulin Secretion from Hepatitis E Virus ORF3-expressing Human Hepatoma Cells Is Mediated by the Tumor Susceptibility Gene 101^*

From the Virology Group, International Centre for Genetic Engineering & Biotechnology, Aruna Asaf Ali Road, New Delhi 110067, India

Viruses are known to exploit the host cell machinery for their benefit during different stages of their life cycle within the infected host. One of the major challenges for a virus during the early stages of infection is to escape recognition by the host immune system. Viruses have adopted many novel strategies to evade the host immune response or to create an immune suppressed environment. An earlier study in our laboratory has demonstrated that the ORF3 protein of the hepatitis E virus expedites the secretion of ₁ microglobulin, an immunosuppressant molecule. Based on this observation, we proposed that enhanced secretion of ₁ microglobulin may help maintain an immunosuppressed milieu around the infected hepatocyte (Tyagi, S., Surjit, M., Roy, A. K., Jameel, S., and Lal, S. K. (2004) J. Biol. Chem. 279, 29308–29319). In the present study, we discovered that the ability of the ORF3 protein to expedite ₁ microglobulin secretion is attributed to the PSAP motif present at the C terminus of the former. The ORF3 protein was able to associate with the tumor susceptibility gene 101 (TSG101) through the PSAP motif. Further, a PSAP motif-mutated ORF3 protein was unable to associate with TSG101 and also lost its ability to enhance the secretion of ₁ microglobulin. In addition, the ORF3 protein was found to associate simultaneously with TSG101 and ₁ microglobulin because all three of them were co-precipitated as a ternary complex. Finally, a dominant negative mutant of the VPS4 protein was shown to block the enhanced ₁ microglobulin secretion in ORF3-expressing hepatocytes. These results suggest a mechanism by which the ORF3 protein exploits the endosomal sorting machinery to enhance the secretion of an immunosuppressant molecule (₁ microglobulin) from the cultured hepatocytes.

Received for publication, August 31, 2005 , and in revised form, January 3, 2006.

^* This work was supported by internal funds from International Centre for Genetic Engineering and Biotechnology and in part from a Swedish International Development Agency grant (to S. K. L.). 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 Post-doctoral fellow on the Swedish International Development Agency grant.

² Council of Scientific and Industrial Research senior research fellow on the Swedish International Development Agency grant.

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

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