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Journal of Virology, October 2007, p. 11096-11105, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01249-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

A Rab-GAP TBC Domain Protein Binds Hepatitis C Virus NS5A and Mediates Viral Replication{triangledown}

Ella H. Sklan,1 Kirk Staschke,2 Tina M. Oakes,2 Menashe Elazar,1 Mark Winters,1 Benjamin Aroeti,1,{dagger} Tsafi Danieli,1,{dagger} and Jeffrey S. Glenn1,3*

Division of Gastroenterology and Hepatology, Stanford University School of Medicine,1 Veterans Administration Medical Center, Palo Alto, California,3 Lilly Research Laboratories, Indianapolis, Indiana2

Received 8 June 2007/ Accepted 16 July 2007

Hepatitis C virus (HCV) is an important cause of liver disease worldwide. Current therapies are inadequate for most patients. Using a two-hybrid screen, we isolated a novel cellular binding partner interacting with the N terminus of HCV nonstructural protein NS5A. This partner contains a TBC Rab-GAP (GTPase-activating protein) homology domain found in all known Rab-activating proteins. As the first described interaction between such a Rab-GAP and a viral protein, this finding suggests a new mechanism whereby viruses may subvert host cell machinery for mediating the endocytosis, trafficking, and sorting of their own proteins. Moreover, depleting the expression of this partner severely impairs HCV RNA replication with no obvious effect on cell viability. These results suggest that pharmacologic disruption of this NS5A-interacting partner can be contemplated as a potential new antiviral strategy against a pathogen affecting nearly 3% of the world's population.

* Corresponding author. Mailing address: Stanford University School of Medicine, CCSR 3115A, 269 Campus Drive, Palo Alto, CA 94305-5187. Phone: (650) 725-3373. Fax: (650) 723-3032. E-mail: jeffrey.glenn{at}stanford.edu

{triangledown} Published ahead of print on 8 August 2007.

{dagger} Present address: Alexander Silberman Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem, Israel.

Journal of Virology, October 2007, p. 11096-11105, Vol. 81, No. 20
0022-538X/07/$08.00+0     doi:10.1128/JVI.01249-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Liu, Z., Yang, F., Robotham, J. M., Tang, H. (2009). Critical Role of Cyclophilin A and Its Prolyl-Peptidyl Isomerase Activity in the Structure and Function of the Hepatitis C Virus Replication Complex. J. Virol. 83: 6554-6565 [Abstract] [Full Text]  
  • Sklan, E. H., Serrano, R. L., Einav, S., Pfeffer, S. R., Lambright, D. G., Glenn, J. S. (2007). TBC1D20 Is a Rab1 GTPase-activating Protein That Mediates Hepatitis C Virus Replication. J. Biol. Chem. 282: 36354-36361 [Abstract] [Full Text]  


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