SUMOylation and ubiquitination reciprocally regulate SMCHD1 antiviral activity against herpes simplex virus 1

  • PLoS Pathog. 2026 Jun 24;22(6):e1014371. doi: 10.1371/journal.ppat.1014371.
Xuezhang Tian  1  2  3 ,  Xinyue Wang  1  2 ,  Shaowei Wang  1  2 ,  Yunhong Zhong  1  2 ,  Yanlin Xia  1 ,  Yang Chen  1 ,  Ling He  1  2 ,  Dongli Pan  4  5 ,  Ke Lan  2  6 ,  Junjie Zhang  1  2  3
Affiliations
  • 1. State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, State Key Laboratory of Virology and Biosafety, Medical Research Institute, Wuhan University, Wuhan, China.
  • 2. Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan, China.
  • 3. Hubei Key Laboratory of Tumor Biological Behavior, Hubei Province Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, Wuhan, China.
  • 4. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 5. Department of Medical Microbiology and Parasitology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 6. State Key Laboratory of Virology and Biosafety, School of Life Sciences, Wuhan University, Wuhan, China.
PMID: 42341060 DOI: 10.1371/journal.ppat.1014371
Abstract

Host restriction factors serve as intrinsic barriers against viral Infection, and are frequently counteracted by viral antagonists. Previous studies, including our own, have identified SMCHD1 as a restriction factor that suppresses the replication of multiple viruses. Here, we reveal that the Antiviral activity of SMCHD1 is dynamically regulated by two different post-translational modifications. SUMOylation of SMCHD1 promotes its association with the viral genome and enhances its Antiviral activity. In contrast, during herpes simplex virus 1 (HSV-1) Infection, the viral E3 Ligase ICP0 induces SMCHD1 ubiquitination and proteasomal degradation, thereby relieving viral restriction. Loss of ICP0 stabilizes SMCHD1 and leads to marked accumulation of SUMOylated SMCHD1, rendering ICP0-deficient HSV-1 more sensitive to SMCHD1-mediated inhibition. Together, our findings uncover a reciprocal SUMO-ubiquitin regulatory mechanism that governs SMCHD1 Antiviral activity and highlight a refined virus-host arms race centered on biphasic modification of a single restriction factor.

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