2. Academic Validation
  3. ICP22-defined condensates mediate RNAPII deubiquitylation by UL36 and promote HSV-1 transcription

ICP22-defined condensates mediate RNAPII deubiquitylation by UL36 and promote HSV-1 transcription

  • Cell Rep. 2024 Oct 22;43(10):114792. doi: 10.1016/j.celrep.2024.114792.
Hansong Qi 1,  Mengqiu Yin 1,  Feng Xiong 2,  Xiaoli Ren 3,  Kangning Chen 1,  Hai-Bin Qin 4,  Erlin Wang 5,  Guijun Chen 5,  Liping Yang 5,  Long-Ding Liu 6,  Hui Zhang 7,  Xia Cao 8,  Nigel W Fraser 9,  Min-Hua Luo 10,  Wen-Bo Zeng 11,  Jumin Zhou 12
Affiliations

Affiliations

  • 1 Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Yunnan 650201, China.
  • 2 State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Wuhan Institute of Physics and Mathematics, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China.
  • 3 Maize Research Institute, Sichuan Agricultural University, Chengdu 611130, China.
  • 4 Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China.
  • 5 Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China.
  • 6 Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, Kunming 650118, China.
  • 7 Department of Ophthalmology, The First Affiliated Hospital Kunming Medical University, Kunming 650032, China.
  • 8 Key Laboratory of Second Affiliated Hospital of Kunming Medical University, Kunming 650000, China.
  • 9 Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 10 State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: luomh@wh.iov.cn.
  • 11 Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China; State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China. Electronic address: zengwb@wh.iov.cn.
  • 12 Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China; KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases, Kunming 650223, China. Electronic address: zhoujm@mail.kiz.ac.cn.
PMID: 39383039 DOI: 10.1016/j.celrep.2024.114792
Abstract

Herpes simplex virus type I (HSV-1) Infection leads to RNA polymerase II (RNAPII) degradation and host transcription shutdown. We show that ICP22 defines the virus-induced chaperone-enriched (VICE) domain through liquid-liquid phase separation. Condensate-disrupting point mutations of ICP22 increase ubiquitin modification of RNAPII Ser-2P; reduce its level and occupancy on viral genes; impair viral gene expression, particularly late genes; and severely reduce viral titers. When Proteasome activity is blocked, ubiquitinated RNAPII Ser-2P and the viral UL36 begin to accumulate in the ICP22 condensates. The Ubiquitin-Specific Protease (USP) Deubiquitinase domain of UL36 interacts with and erases ubiquitin modification from RNAPII Ser-2P, protecting it from degradation in infected cells. A virus carrying a catalytic mutant of the UL36 USP diminishes cellular RNAPII Ser-2P levels, viral transcription, and growth. Thus, ICP22 condensates are processing centers where RNAPII Ser-2P is recruited to be deubiquitinated to ensure viral transcription when host transcription is disrupted following Infection.

Keywords

CP: Immunology; CP: Molecular biology; HSV-1; ICP22; RNAPII; deubiquitylation; phase separation; viral transcription.

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