La protein required for internal ribosome entry site-directed translation is a potential therapeutic target for hepatitis C virus replication.
BACKGROUND
Translation of the hepatitis C virus (HCV) is mediated by an internal ribosome entry site (IRES). Here, we analyzed the functional relevance of La protein for replication of HCV using an infectious HCV clone, JFH-1.


METHODS
A single-nucleotide mutation from A to U was introduced at the 338th nucleotide in the stem-loop domain IV structure of HCV IRES, which stabilized stem-loop IV and abolished translation and replication of JFH-1 almost completely.


RESULTS
During JFH-1 replication, translation initiation factors required for HCV IRES activity, including La protein, polypyrimidine tract binding protein (PTB), PSMA7, and PCBP2, were significantly induced in Huh-7.5 cells. Interestingly, JFH-1 infection increased telomerase activity and induced the expression of human telomerase RNA (hTR) in Huh-7.5 cells. In 37 tissue specimens from patients with chronic hepatitis C, La protein significantly correlated with the representative essential telomerase components hTR, p23, and HSP90 (P<.001). Recombinant adenovirus that expressed short-hairpin RNA against La protein successfully suppressed the levels of La protein and core protein of JFH-1 to 30% of that in the control cells.


CONCLUSIONS
HCV infection might be strongly related to telomerase activity in the liver through La protein induction. Inhibition of La protein substantially repressed JFH-1 replication; therefore, La protein is a potential therapeutic target for HCV.
Shirasaki
Takayoshi
T
Department of Gastroenterology, Division of Health Medicine, Graduate School of Medicine, Kanazawa University, Kanazawa 920-8641, Japan.
Honda
Masao
M
Mizuno
Hideki
H
Shimakami
Tetsuro
T
Okada
Hikari
H
Sakai
Yoshio
Y
Murakami
Seishi
S
Wakita
Takaji
T
Kaneko
Shuichi
S
D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D034622:RNA Interference; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D054334:Viral Regulatory and Accessory Proteins; D014779:Virus Replication; D000097585:SS-B Antigen
D001324:Autoantigens; D012261:Ribonucleoproteins; D019098:Telomerase; D054334:Viral Regulatory and Accessory Proteins; D000097585:SS-B Antigen