한빛사논문
- 조회1,804
Geon-woo Kim1, Hasan Imam1, Mohsin Khan1, Saiful Anam Mir1, Seong-Jun Kim2, Seung Kew Yoon3,4, Wonhee Hur3, and Aleem Siddiqui1,*
1Division of Infectious Diseases, , Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
2Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea
3The Catholic University Liver Research Center, College of Medicine, The Catholic University of Korea, Seoul, South Korea (06591)
4Division of Hepatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, the Catholic University of Korea, Seoul, South Korea (06591)
*Corresponding author
Abstract
Background & Aims
Epitranscriptomic modification of RNA has emerged as the most prevalent form of regulation of gene expression which affects development, differentiation, metabolism, viral infections, and most notably cancer. We have previously shown that Hepatitis B virus (HBV) transcripts are modified by N6 methyladenosine (m6A) addition. HBV also affects m6A modification of several host RNAs, including phosphatase and tensin homolog (PTEN), a well‐known tumor suppressor. PTEN plays a critical role in antiviral innate immunity and the development of hepatocellular carcinoma (HCC). Reports have shown that PTEN controlled IRF‐3 nuclear localization by negative phosphorylation of IRF‐3 at Ser97, and PTEN reduced carcinogenesis by inhibiting the phosphatidylinositol‐3‐kinase (PI3K)/AKT pathway.
Approach & Results
Here, we show that HBV significantly increases the m6A modification of PTEN RNA, which contributes to its instability with a corresponding decrease in PTEN protein levels. This is reversed in cells, in which m6A methyltransferases (METTL3/14) expression, is silenced. PTEN expression directly increases activated IRF‐3 nuclear import and subsequent interferon (IFN) synthesis. In the absence of PTEN, IRF‐3 dephosphorylation at Ser97 site is decreased and IFN synthesis is crippled. In chronic‐HBV patient biopsy samples, m6A modified PTEN mRNA levels were uniformly upregulated with a concomitant decrease of PTEN mRNA levels. HBV gene expression also activated PI3K/AKT pathway by regulating PTEN mRNA stability in HCC cell lines.
Conclusions
Thus, m6A epitranscriptomic regulation of PTEN by HBV affects innate immunity via inhibiting IRF‐3 nuclear import and the development of HCC through activating PI3K/AKT pathway. Our studies collectively provide new insights into the mechanisms of HBV‐directed immune evasion and HBV‐associated hepatocarcinogenesis via m6A modification of the host PTEN mRNAs.
논문정보
- Research article
- 2020년 05월 (BRIC 등록일 2020-05-14)
- 국내+국외 연구진
- 생명과학 > 감염생물학
댓글 작성 로그인
팝업 닫기관련 링크
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
