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서울대학교

Proc. Natl. Acad. Sci. USA, Jun 17 2025, 122 (24) | https://doi.org/10.1073/pnas.2508475122 N6-methyladenosine modification of HCMV IE1 transcript promotes the repressive state of viral genome to achieve latent infection

Heena Jeong ^{1 2}, Nagyeong Yeo ¹, Hyeonseo Hwang ¹, Junhyun Park ^{1 2}, Daehyun Baek¹, Kwangseog Ahn ^{1 2 3 *}

¹School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea.
²Center for RNA Research, Institute for Basic Science, Seoul 08826, Republic of Korea.
³Institute for Virus Research, Seoul National University, Seoul 08826, Republic of Korea.

^*Corresponding author: correspondence to Kwangseog Ahn

Abstract

Human cytomegalovirus (HCMV) is a prevalent pathogen that chronically infects the majority of human population. Among the many features that allow such widespread HCMV infection, one is its ability to maintain a transcriptionally dormant immune-evasive state called latency by suppressing its own major immediate early promoter (MIEP) via epigenetic alterations. In this study, we show a mechanism of MIEP regulation in which the major immediate early (MIE) gene product, immediate early 1 (IE1) transcript, downregulates its own promoter activity in an m⁶A modification-dependent manner. We found that the loss of the m⁶A writer, METTL3, in host cells impedes latency establishment in these cells. Through transcriptome-wide m⁶A profiling of latently infected monocytes, we identified that the major immediate early gene product IE1 transcript is m⁶A-modified during latent infection. Using IE1-specific m⁶A-abolished mutants, we found that m⁶A modification of the IE1 transcript was necessary for the efficient repression of MIEP, and these mutant viruses exhibited a significant defect in establishing latency and progressed toward lytic-like infection in the human monocytic cell line (THP-1) and primary CD14+ monocytes. Our findings demonstrate that HCMV exploits the host m⁶A machinery to suppress its own lytic program to establish latency and uncover an unexpected role of immediate early gene messenger RNA (mRNA) in regulating its own expression.

논문정보

형식Research article
게재일2025년 06월 (BRIC 등록일 2025-06-11)
연구진국내 연구진
분야 생명과학 > 감염생물학

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