김건우 (University of California, San Diego)

한빛사논문

조회738

University of California, San Diego

CV File 163 kb

Proc. Natl. Acad. Sci. USA, March 9, 2021, 118(10) : e2022024118 | https://doi.org/10.1073/pnas.2022024118 N6-methyladenosine modification of HCV RNA genome regulates cap-independent IRES-mediated translation via YTHDC2 recognition

Geon-Woo Kim^a and Aleem Siddiqui^a,1

^aDivision of Infectious Diseases, Department of Medicine, University of California San Diego, La Jolla, CA 92093

¹To whom correspondence may be addressed.

Abstract

Hepatitis C virus (HCV) infections are associated with the risk of progression to fibrosis, cirrhosis, and hepatocellular carcinoma. The HCV RNA genome is translated by an internal ribosome entry site (IRES)-dependent mechanism. The structure and function of the HCV IRES have been investigated by both biological and biophysical criteria. Recently, the role of N6-methyladenosine (m6A) in cellular RNA and viral transcripts has been intensely investigated. The HCV RNA genome is m6A-methylated, and this modification regulates the viral life cycle. In this study, we investigated the role of m6A modification of the HCV genome in the IRES-dependent translation function by mutating m6A consensus motifs (DRACH) within the IRES element in stem–loop III and IV regions and studied their effect on translation initiation. There are several DRACH motifs within the IRES element. Of these, the DRACH motif at nucleotide (nt) 329-333, located about 7 nt upstream of initiator AUG (iAUG) codon, regulates IRES-mediated translation initiation. Mutational analysis showed that m6A methylation of the adenosine at nt 331 is essential for the IRES-dependent translation. m6A reader protein YTHDC2, containing the RNA helicase domain, recognizes m6A-methylated adenosine at nt 331 and, in concert with the cellular La antigen, supports HCV IRES-dependent translation. The RNA helicase dead YTHDC2 (E332Q) mutant failed to stimulate HCV translation initiation. This report highlights the functional roles of m6A modification and YTHDC2 in the HCV IRES-dependent translation initiation, thus offering alternative therapeutic avenues to interfere with the infectious process.

N6-methyladenosine modification, HCV, HCV IRES translation, cap-independent translation, YTHDC2

논문정보

형식Research article
게재일2021년 03월 (BRIC 등록일 2021-04-02)
연구진국외 연구진
분야 생명과학 > 감염생물학

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