A Rab-GAP TBC domain protein binds hepatitis C virus NS5A and mediates viral replication.
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.
Division of Gastroenterology and Hepatology, Stanford University School of Medicine, CCSR 3115A, 269 Campus Drive, Palo Alto, CA 94305-5187, USA.
Ella H
EH
Sklan
Kirk
K
Staschke
Tina M
TM
Oakes
Menashe
M
Elazar
Mark
M
Winters
Benjamin
B
Aroeti
Tsafi
T
Danieli
Jeffrey S
JS
Glenn
D001665:Binding Sites; D002470:Cell Survival; D020690:GTPase-Activating Proteins; D015723:Gene Library; D016174:Hepacivirus / Q000737:chemistry / Q000502:physiology; D006801:Humans; D008099:Liver / Q000473:pathology / Q000821:virology; D011485:Protein Binding; D020798:Two-Hybrid System Techniques; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D014779:Virus Replication; D020691:rab GTP-Binding Proteins / Q000378:metabolism*; D012324:RNA-Dependent RNA Polymerase
D020690:GTPase-Activating Proteins; D017361:Viral Nonstructural Proteins; D020691:rab GTP-Binding Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase