MOA Key Laboratory of Animal Virology, Zhejiang University Center for Veterinary Sciences, Hangzhou, China.
Clinical Research Institute, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, China.
Nat Commun. 2024 Oct 16;15(1):8927. doi: 10.1038/s41467-024-53100-z.
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.
自噬在冠状病毒感染中发挥双重作用，既能促进前病毒成分的清除（病毒噬作用），也能促进抗病毒因子（如线粒体）的清除（线粒体噬作用），从而导致复杂的免疫逃避机制。了解在冠状病毒感染中控制自噬降解有害或有益底物之间转换的机制对于开发精确的药物靶点来治疗病毒诱导的疾病至关重要。然而，这个转换机制在很大程度上仍不清楚。我们使用双荧光分割测定法鉴定出 PDPK1 是先天免疫的负调控因子，通过磷酸化 SQSTM1 上的 T138 将病毒噬作用转变为线粒体噬作用。值得注意的是，靶向 PDPK1 的肽通过增强病毒噬作用和抑制线粒体噬作用来恢复先天免疫，从而保护雌性小鼠免受致死性感染，从而抑制各种 RNA 病毒的复制。这些发现强调了 PDPK1 通过协调从病毒噬作用到线粒体噬作用的转变在先天免疫中的有害作用，将 PDPK1 定位为一种有前途的药理学靶点，可有效对抗广泛的病毒感染。
