Hepatitis C virus core protein inhibits E6AP expression via DNA methylation to escape from ubiquitin-dependent proteasomal degradation.
The E6-associated protein (E6AP) is a ubiquitin ligase that mediates ubiquitination and proteasomal degradation of hepatitis C virus (HCV) core protein. Given the role of HCV core protein as a major component of the viral nucleocapsid, as well as a multifunctional protein involved in viral pathogenesis and hepatocarcinogenesis, HCV has likely evolved a strategy to counteract the host anti-viral defense mechanism of E6AP and maximize its potential to produce infectious virus particles. In the present study, we found that HCV core protein derived from either ectopic expression or HCV infection inhibits E6AP expression via promoter hypermethylation in human hepatocytes. As a result, the potential of E6AP to ubiquitinate and degrade HCV core protein through the ubiquitin-proteasome system was severely impaired, which in turn led to stimulation of virus propagation. The effects of HCV core protein were almost completely abolished when the E6AP level was restored by ectopic expression of E6AP, treatment with a universal DNA methyltransferase (DNMT) inhibitor, 5-Aza-2'dC, or knock-down of DNMT1. In conclusion, HCV core protein inhibits E6AP expression via DNA methylation to protect itself from ubiquitin-dependent proteasomal degradation and stimulate virus propagation, providing a potential target for the development of anti-viral drugs against HCV.
Department of Microbiology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Juri
J
Kwak
Department of Microbiology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Joo Hee
JH
Shim
Department of Microbiology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea.
Indira
I
Tiwari
Department of Microbiology, College of Natural Science, Pusan National University, Busan 609-735, Republic of Korea. Electronic address: kljang@pusan.ac.kr.
Kyung Lib
KL
Jang
D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056945:Hep G2 Cells; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology* / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D034622:RNA Interference; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D014758:Viral Core Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D004791:Enzyme Inhibitors; D014758:Viral Core Proteins; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C471639:UBE3A protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex
Core protein; DNA methylation; E6-associated protein; Hepatitis C virus; Ubiquitin-proteasome system