Hepatitis C Virus RNA Functionally Sequesters miR-122

被引:277
作者
Luna, Joseph M. [1 ,2 ,3 ]
Scheel, Troels K. H. [1 ,4 ,5 ,6 ]
Danino, Tal [1 ,7 ]
Shaw, Katharina S. [1 ]
Mele, Aldo [2 ,3 ]
Fak, John J. [2 ,3 ]
Nishiuchi, Eiko [1 ]
Takacs, Constantin N. [1 ,8 ]
Catanese, Maria Teresa [1 ]
de Jong, Ype P. [1 ,9 ]
Jacobson, Ira M. [9 ]
Rice, Charles M. [1 ]
Darnell, Robert B. [2 ,3 ,10 ]
机构
[1] Rockefeller Univ, Ctr Study Hepatitis C, Lab Virol & Infect Dis, New York, NY 10065 USA
[2] Rockefeller Univ, Lab Mol Neurooncol, New York, NY 10065 USA
[3] Rockefeller Univ, Howard Hughes Med Inst, New York, NY 10065 USA
[4] Copenhagen Univ Hosp, Dept Infect Dis, Copenhagen Hepatitis C Program CO HEP, Hvidovre, Denmark
[5] Copenhagen Univ Hosp, Clin Res Ctr, Hvidovre, Denmark
[6] Univ Copenhagen, Fac Hlth & Med Sci, Dept Int Hlth Immunol & Microbiol, DK-2200 Copenhagen N, Denmark
[7] MIT, Hlth Sci & Technol, Cambridge, MA 02139 USA
[8] Rockefeller Univ, Lab Cellular Biophys, New York, NY 10065 USA
[9] Weill Cornell Med Coll, Div Gastroenterol & Hepatol, Ctr Study Hepatitis C, New York, NY 10065 USA
[10] New York Genome Ctr, New York, NY 10013 USA
关键词
SINGLE-NUCLEOTIDE RESOLUTION; HITS-CLIP; CERNA HYPOTHESIS; BINDING PROTEIN; MICRORNA; IDENTIFICATION; ARGONAUTE; INFECTION; GENES; SITES;
D O I
10.1016/j.cell.2015.02.025
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hepatitis C virus (HCV) uniquely requires the liver-specific microRNA-122 for replication, yet global effects on endogenous miRNA targets during infection are unexplored. Here, high-throughput sequencing and crosslinking immunoprecipitation (HITS-CLIP) experiments of human Argonaute (AGO) during HCV infection showed robust AGO binding on the HCV 5'UTR at known and predicted miR-122 sites. On the human transcriptome, we observed reduced AGO binding and functional mRNA de-repression of miR-122 targets during virus infection. This miR-122 "sponge'' effect was relieved and redirected to miR-15 targets by swapping the miRNA tropism of the virus. Single-cell expression data from reporters containing miR-122 sites showed significant derepression during HCV infection depending on expression level and site number. We describe a quantitative mathematical model of HCV-induced miR-122 sequestration and propose that such miR-122 inhibition by HCV RNA may result in global derepression of host miR-122 targets, providing an environment fertile for the long-term oncogenic potential of HCV.
引用
收藏
页码:1099 / 1110
页数:12
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