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Nat. Microbiol., Aug 08 2025, | https://doi.org/10.1038/s41564-025-02078-5
Human cytomegalovirus long non-coding RNA counteracts nuclear cGAS to facilitate immune evasion
Sungwon Lee1,2, Sungchul Kim1,3, Hyejun Kim 1,2, Dohoon Lee4, Dongjoon Jeong1,2, Hyewon Kim1,2, Junhyun Park1,2,5, Kiwon Park1,2, Jin Hur6, Sun Kim7, V. Narry Kim1,2 & Kwangseog Ahn1,2,8
1Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
2School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
3Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
4Bioinformatics Institute, Seoul National University, Seoul, Republic of Korea.
5The Research Institute of Basic Sciences, Seoul National University, Seoul, Republic of Korea.
6PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan, Republic of Korea.
7Department of Computer Science and Engineering, Seoul National University, Seoul, Republic of Korea.
8SNU Institute for Virus Research, Seoul National University, Seoul, Republic of Korea.
Corresponding author
Correspondence to Kwangseog Ahn.
1Center for RNA Research, Institute for Basic Science, Seoul, Republic of Korea.
2School of Biological Sciences, Seoul National University, Seoul, Republic of Korea.
3Department of Life Sciences, Pohang University of Science and Technology, Pohang, Republic of Korea.
4Bioinformatics Institute, Seoul National University, Seoul, Republic of Korea.
5The Research Institute of Basic Sciences, Seoul National University, Seoul, Republic of Korea.
6PNU GRAND Convergence Medical Science Education Research Center, Pusan National University School of Medicine, Yangsan, Republic of Korea.
7Department of Computer Science and Engineering, Seoul National University, Seoul, Republic of Korea.
8SNU Institute for Virus Research, Seoul National University, Seoul, Republic of Korea.
Corresponding author
Correspondence to Kwangseog Ahn.
Abstract
Viruses have evolved diverse immune evasion strategies, including the targeting of host pattern recognition receptors. The role of viral non-coding RNAs in modulating pattern recognition receptor activity is unclear. Here we show that human cytomegalovirus (HCMV) produces long non-coding RNA4.9 that counteracts the nuclear cyclic GMP-AMP synthase (cGAS)-mediated immune response to facilitate viral infection in human foreskin fibroblasts. RNA4.9 interacts with host cGAS via its 75-nucleotide RNA region with predicted hairpin loops. Binding of RNA4.9 to cGAS inhibits cGAS enzymatic activity as well as downstream interferon response and facilitates productive viral replication. Sterically blocking the folding of the 75-nucleotide region with antisense oligonucleotides during HCMV infection restores cGAS activity and impairs viral replication. In addition, we found that the specific localization of RNA4.9, which concentrates near HCMV DNA, is correlated with its efficient binding to cGAS and subsequent immune suppression. Our findings identify viral non-coding RNAs as key regulators of cGAS and highlight their potential as therapeutic targets.
논문정보
- Research article
- 2025년 08월 (BRIC 등록일 2025-08-11)
- 국내 연구진
- 생명과학 > 면역학
관련 보도자료
긴 논코딩 RNA에 의한 만성감염 바이러스의 선천면역 회피 기전 규명
본 연구진은 HCMV lncRNA가 숙주의 선천면역 유발을 차단함을 규명했다. 4.9 kb 크기의 lncRNA(이하 RNA4.9라 칭함)가 바이러스 DNA 감지 센서인 cGAS를 고립시켜 선천면역을 무력화함을 발견했다. cGAS와 결합하는 RNA4.9의 부위를 표적하는 안티센스 올리고머(AOS)를 처리하면 cGAS-RNA4.9 결합이 저해되고 cGAS-매개 선천면역이 복원되어 바이러스 복제가 억제되었다. 이는 ASO 기반 HCMV 치료제 개발 가능성을 제시한다.
- Bio통신원
- 2025. 08. 11
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