Host transcriptional corepressor TLE1 is commonly exploited by RNA viruses for replication

  • Mol Cell. 2026 Aug 6;86(15):2950-2965.e9. doi: 10.1016/j.molcel.2026.06.043.
Xiaomeng Yang  1 ,  Haoran Sun  2 ,  Peng Luo  3 ,  Kailai Li  4 ,  Tong-Yun Wang  5 ,  Qian Guo  1 ,  Hehe Cao  1 ,  Xiaoyang Shu  1 ,  Bo Qin  6 ,  Min Guo  7 ,  Ming Yan  8 ,  Kun Huang  1 ,  Jiahui Zou  1 ,  Zi-Wei Ye  9 ,  Hin Chu  10 ,  Jasper Fuk-Woo Chan  10 ,  Dong-Yan Jin  11 ,  Bi Shi  8 ,  Sheng Cui  6 ,  Honglin Chen  12 ,  Kwok-Yung Yuen  10 ,  Shuofeng Yuan  13
Affiliations
  • 1. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
  • 2. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China.
  • 3. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, China.
  • 4. Department of Oncology, Zhujiang Hospital, Southern Medical University, 253 Industrial Avenue, Guangzhou 510282, China.
  • 5. Department of Pediatrics, University of California, San Diego, La Jolla, CA 92093, USA.
  • 6. NHC Key Laboratory of Systems Biology of Pathogens, Institute of Pathogen Biology Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
  • 7. Center Laboratory, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510282, China.
  • 8. Institute of Pathogen Biology and Immunology, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China.
  • 9. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
  • 10. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Pandemic Research Alliance Unit at the University of Hong Kong, Pokfulam, Hong Kong, China.
  • 11. School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China.
  • 12. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Pandemic Research Alliance Unit at the University of Hong Kong, Pokfulam, Hong Kong, China.
  • 13. Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Department of Infectious Diseases and Microbiology, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518000, China; Centre for Virology, Vaccinology and Therapeutics, Hong Kong Science and Technology Park, Hong Kong, China; State Key Laboratory of Emerging Infectious Diseases, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China; Pandemic Research Alliance Unit at the University of Hong Kong, Pokfulam, Hong Kong, China. Electronic address: [email protected].
PMID: 42480521 DOI: 10.1016/j.molcel.2026.06.043
Abstract

Viral genomes encode transcriptional regulators that alter the expression of host genes to facilitate virus replication, and the comprehensive regulatory network they form is largely elusive. Utilizing influenza A virus (IAV) as a model, we demonstrate that the viral nucleoprotein (NP) harnesses the host transcriptional corepressor TLE1 to enhance viral polymerase activity while suppressing the cellular innate response. NP-TLE1 recognition was realized via a conserved basic helix-loop-helix (bHLH)-like motif across IAV subtypes, which subsequently recruited another transcription factor, Kruppel-like factor 4 (KLF4), to suppress Antiviral signaling. Blockage of the NP-TLE1 interaction by a peptide AH49A provided Antiviral protection in vitro and in vivo. Moreover, the NP-TLE1-KLF4 axis was widely observed across various RNA viruses, as evidenced by the presence of a bHLH-like motif in the SARS-CoV-2 nucleocapsid protein. Loss-of-function substitutions in the bHLH-like motif attenuated the replication of both IAV and SARS-CoV-2. Our study reveals how RNA viruses exploit the components of the host transcription machinery to facilitate virus replication.

Keywords
TLE1; antiviral peptide; transcriptional corepressor; viruses.
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