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

Yahui Li, Chunyan Li, Chenchen Zhao, Jiayu Wu, Ya Zhu, Fei Wang, Jiepeng Zhong, Yan Yan, Yulan Jin, Weiren Dong, Jinyang Chen, Xianghong Yang, Jiyong Zhou () and Boli Hu ()
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Yahui Li: Zhejiang University Center for Veterinary Sciences
Chunyan Li: Zhejiang University Center for Veterinary Sciences
Chenchen Zhao: Zhejiang University Center for Veterinary Sciences
Jiayu Wu: Zhejiang University Center for Veterinary Sciences
Ya Zhu: Zhejiang University Center for Veterinary Sciences
Fei Wang: Zhejiang University Center for Veterinary Sciences
Jiepeng Zhong: Zhejiang University Center for Veterinary Sciences
Yan Yan: Zhejiang University Center for Veterinary Sciences
Yulan Jin: Zhejiang University Center for Veterinary Sciences
Weiren Dong: Zhejiang University Center for Veterinary Sciences
Jinyang Chen: Zhejiang University Center for Veterinary Sciences
Xianghong Yang: Hangzhou Medical College
Jiyong Zhou: Zhejiang University Center for Veterinary Sciences
Boli Hu: Zhejiang University Center for Veterinary Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53100-z

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