Wang Shanshan, Du Tongtong, Yan Jun, Zheng Yingcheng, Tang Yinglian, Wu Juejie, Xu Qian, Xu Shanshan, Liu Luo, Chen Xiong, Han Song, Yin Jun, Peng Biwen, He Xiaohua, Liu Wanhong
Hubei Province Key Laboratory of Allergy and Immunology, Taikang Medical School (School of Basic Medical Sciences), Wuhan University, Wuhan, 430071, China.
Department of Laboratory Medicine, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430071, China.
Retrovirology. 2025 May 2;22(1):7. doi: 10.1186/s12977-025-00664-3.
Prototype foamy virus (PFV) is a complex retrovirus that can maintain latent infection for life after viral infection of the host. However, the mechanism of latent infection with PFV remains unclear. Our previous studies have shown that PFV promotes autophagy flux, but whether PFV causes mitophagy remains unclear.
In this study, we demonstrated that PFV infection damages mitochondria, increases mitochondria reactive oxygen species (mtROS) production, and induces mitophagy in a time-dependent manner. Further investigation revealed that PFV Gag is a crucial protein responsible for triggering mitophagy. The overexpression of Gag leads to mitochondrial damage and stimulates mitophagy in a dose-dependent manner. Additionally, overexpression of Gag activates the PINK1-Parkin signaling pathway, while the knockdown of Parkin inhibits Gag-induced mitophagy. Furthermore, Rab5a was significantly upregulated in cells overexpressed Gag, and the inhibition of Rab5a reversed the effects of Gag-induced mitophagy.
Our data suggested that PFV can induce mitophagy and Gag induces Parkin-dependent mitophagy by upregulating Rab5a. These findings not only enhance a better understanding of the foamy virus infection mechanisms but also provide critical insights into novel virus-host cell interactions.
原型泡沫病毒（PFV）是一种复杂的逆转录病毒，在宿主被病毒感染后可终生维持潜伏感染。然而，PFV潜伏感染的机制仍不清楚。我们之前的研究表明，PFV促进自噬通量，但PFV是否导致线粒体自噬仍不清楚。
在本研究中，我们证明PFV感染会损害线粒体，增加线粒体活性氧（mtROS）的产生，并以时间依赖性方式诱导线粒体自噬。进一步研究发现，PFV Gag是引发线粒体自噬的关键蛋白。Gag的过表达导致线粒体损伤，并以剂量依赖性方式刺激线粒体自噬。此外，Gag的过表达激活了PINK1-Parkin信号通路，而Parkin的敲低抑制了Gag诱导的线粒体自噬。此外，Rab5a在过表达Gag的细胞中显著上调，Rab5a的抑制逆转了Gag诱导的线粒体自噬的作用。
我们的数据表明，PFV可诱导线粒体自噬，Gag通过上调Rab5a诱导Parkin依赖性线粒体自噬。这些发现不仅有助于更好地理解泡沫病毒的感染机制，还为新型病毒-宿主细胞相互作用提供了关键见解。
