2. Academic Validation
  3. TOLLIP inhibits the replication of PEDV by autophagic degradation of Nsp9

TOLLIP inhibits the replication of PEDV by autophagic degradation of Nsp9

  • Int J Biol Macromol. 2025 Feb 3;304(Pt 1):140631. doi: 10.1016/j.ijbiomac.2025.140631.
Yahui Li 1,  Yutao Zhang 2,  Jiexi Cheng 2,  Jinyang Chen 3,  Zhiwei Lin 3,  Boli Hu 4,  Bin Li 5,  Xianghong Yang 6
Affiliations

Affiliations

  • 1 Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China; MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou 310058, China; Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
  • 2 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou 310058, China.
  • 3 Clinical Research Institute, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China.
  • 4 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou 310058, China. Electronic address: Bolihu@zju.edu.cn.
  • 5 Institute of Veterinary Medicine, Jiangsu Academy of Agricultural Sciences, Key Laboratory of Veterinary Biological Engineering and Technology, Ministry of Agriculture, Nanjing 210014, China. Electronic address: libinana@126.com.
  • 6 Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, Hangzhou 310014, China. Electronic address: jyy623@163.com.
PMID: 39909271 DOI: 10.1016/j.ijbiomac.2025.140631
Abstract

Selective Autophagy plays a crucial role in innate Antiviral immunity by targeting essential viral components and host factors necessary for virus propagation. Among these factors, the nonstructural protein 9 (Nsp9) of Porcine Epidemic Diarrhea Virus (PEDV) is required for viral replication. However, the host factors regulating Nsp9 have remained elusive. In our study, we discovered that Nsp9 undergoes degradation through selective Autophagy. Using coimmunoprecipitation combined with mass spectrometry analysis, we identified Toll-interacting protein (TOLLIP) as an Autophagy cargo receptor binding to Nsp9 and facilitating its autophagic degradation. Additionally, we found that TOLLIP interacts with LC3A, LC3C, and GABARAPL1. Further investigations revealed that Nsp9 specifically enhances the binding of TOLLIP to LC3A, rather than LC3C or GABARAPL1. Importantly, TOLLIP promotes the engulfment of Nsp9 by LC3A-coated autophagosomes and mediates Nsp9 trafficking to lysosomes, ultimately leading to LC3A-dependent degradation of Nsp9. Consequently, TOLLIP suppresses PEDV replication. Overall, our findings highlight the role of TOLLIP in connecting Viral Proteins to LC3A-dependent autophagosome, emphasizing its significance in combating viruses through selective Autophagy.

Keywords

Autophagy cargo receptors; LC3A; PEDV; Selective autophagy; TOLLIP.

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