Human cytomegalovirus harnesses host L1 retrotransposon for efficient replication

Sung-Yeon Hwang, Hyewon Kim, Danielle Denisko, Boxun Zhao, Dohoon Lee, Jiseok Jeong, Jinuk Kim, Kiwon Park, Junhyun Park, Dongjoon Jeong, Sehong Park, Hee-Jung Choi, Sun Kim, Eunjung Alice Lee () and Kwangseog Ahn ()
Additional contact information
Sung-Yeon Hwang: Institute for Basic Science
Hyewon Kim: Institute for Basic Science
Danielle Denisko: Boston Children’s Hospital and Harvard Medical School
Boxun Zhao: Boston Children’s Hospital and Harvard Medical School
Dohoon Lee: Seoul National University
Jiseok Jeong: Institute for Basic Science
Jinuk Kim: Seoul National University
Kiwon Park: Institute for Basic Science
Junhyun Park: Institute for Basic Science
Dongjoon Jeong: Institute for Basic Science
Sehong Park: Institute for Basic Science
Hee-Jung Choi: Seoul National University
Sun Kim: Seoul National University
Eunjung Alice Lee: Boston Children’s Hospital and Harvard Medical School
Kwangseog Ahn: Institute for Basic Science

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: Abstract Genetic parasites, including viruses and transposons, exploit components from the host for their own replication. However, little is known about virus-transposon interactions within host cells. Here, we discover a strategy where human cytomegalovirus (HCMV) hijacks L1 retrotransposon encoded protein during its replication cycle. HCMV infection upregulates L1 expression by enhancing both the expression of L1-activating transcription factors, YY1 and RUNX3, and the chromatin accessibility of L1 promoter regions. Increased L1 expression, in turn, promotes HCMV replicative fitness. Affinity proteomics reveals UL44, HCMV DNA polymerase subunit, as the most abundant viral binding protein of the L1 ribonucleoprotein (RNP) complex. UL44 directly interacts with L1 ORF2p, inducing DNA damage responses in replicating HCMV compartments. While increased L1-induced mutagenesis is not observed in HCMV for genetic adaptation, the interplay between UL44 and ORF2p accelerates viral DNA replication by alleviating replication stress. Our findings shed light on how HCMV exploits host retrotransposons for enhanced viral fitness.

Date: 2024
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DOI: 10.1038/s41467-024-51961-y

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