2. Academic Validation
  3. Coronavirus M protein promotes mitophagy over virophagy by recruiting PDPK1 to phosphorylate SQSTM1 at T138

Coronavirus M protein promotes mitophagy over virophagy by recruiting PDPK1 to phosphorylate SQSTM1 at T138

  • Nat Commun. 2024 Oct 16;15(1):8927. doi: 10.1038/s41467-024-53100-z.
Yahui Li # 1 2,  Chunyan Li # 1,  Chenchen Zhao # 1,  Jiayu Wu 1,  Ya Zhu 1,  Fei Wang 1,  Jiepeng Zhong 1,  Yan Yan 1,  Yulan Jin 1,  Weiren Dong 1,  Jinyang Chen 1,  Xianghong Yang 3,  Jiyong Zhou 4 5,  Boli Hu 6
Affiliations

Affiliations

  • 1 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China.
  • 2 Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
  • 3 Emergency and Critical Care Center, Intensive Care Unit, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
  • 4 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China. jyzhou@zju.edu.cn.
  • 5 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University, Hangzhou, China. jyzhou@zju.edu.cn.
  • 6 MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China. Bolihu@zju.edu.cn.
  • # Contributed equally.
PMID: 39414765 DOI: 10.1038/s41467-024-53100-z
Abstract

Autophagy plays a dual role in coronavirus Infection, facilitating the elimination of either proviral components (virophagy) or Antiviral factors such as mitochondria (Mitophagy), leading to complex mechanisms of immune evasion. Understanding the mechanisms that govern the switch between the autophagic degradation of deleterious or beneficial substrates in coronavirus Infection is crucial for developing precise drug targets to treat virus-induced diseases. However, this switch remains largely unknown. Using a dual split-fluorescence assay, we identify PDPK1 as a negative regulator of innate immunity, directing the transition from virophagy to Mitophagy through the phosphorylation of SQSTM1 at T138. Remarkably, a PDPK1-targeting peptide inhibits the replication of various RNA viruses by restoring innate immunity through enhanced virophagy and suppressed Mitophagy, thereby protecting female mice from lethal infections. These findings underscore the detrimental role of PDPK1 in innate immunity by orchestrating the shift from virophagy to Mitophagy, positioning PDPK1 as a promising pharmacological target for effectively combating a broad spectrum of virus infections.

Figures
Products