RT Journal Article
SR Electronic
T1 USP15 participates in HCV propagation through the regulation of viral RNA translation and lipid droplet formation
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 432930
DO 10.1101/432930
A1 Shinji Kusakabe
A1 Tatsuya Suzuki
A1 Yukari Sugiyama
A1 Saori Haga
A1 Kanako Horike
A1 Makoto Tokunaga
A1 Junki Hirano
A1 Zhang He
A1 David Virya Chen
A1 Hanako Ishiga
A1 Yasumasa Komoda
A1 Chikako Ono
A1 Takasuke Fukuhara
A1 Masahiro Yamamoto
A1 Masahito Ikawa
A1 Takashi Satoh
A1 Shizuo Akira
A1 Tomohisa Tanaka
A1 Kohji Moriishi
A1 Moto Fukai
A1 Akinobu Taketomi
A1 Sachiyo Yoshio
A1 Tatsuya Kanto
A1 Tetsuro Suzuki
A1 Toru Okamoto
A1 Yoshiharu Matsuura
YR 2018
UL http://biorxiv.org/content/early/2018/10/02/432930.abstract
AB Hepatitis C virus (HCV) utilizes cellular factors for an efficient propagation. Ubiquitin is covalently conjugated to the substrate to alter its stability or to modulate signal transduction. In this study, we examined the importance of ubiquitination for HCV propagation. We found that inhibition of de-ubiquitinating enzymes (DUBs) or overexpression of non-specific DUBs impaired HCV replication, suggesting that ubiquitination regulates HCV replication. To identify specific DUBs involved in HCV propagation, we set up an RNAi screening against DUBs and successfully identified ubiquitin-specific protease 15 (USP15) as a novel host factor for HCV propagation. Our studies showed that USP15 is involved in translation of HCV RNA and production of infectious HCV particles. In addition, deficiency of USP15 in human hepatic cell lines (Huh7 and Hep3B/miR122 cells) but not in a non-hepatic cell line (293T cells) impaired HCV propagation, suggesting that USP15 participates in HCV propagation through the regulation of hepatocyte-specific functions. Moreover, we showed that loss of USP15 had no effect on innate immune responses in vitro and in vivo. We also found that USP15-deficient Huh7 cells showed reductions in the sizes and numbers of lipid droplets (LDs), and addition of palmitic acids restored the production of infectious HCV particles. Taken together, these data suggest that USP15 participates in HCV propagation by regulating the translation of HCV RNA and formation of LDs.