Zhu Huazhang, Wang Dawei, Ye Zuodong, Huang Lihong, Wei Wenjie, Chan Kui Ming, Zhang Rongxin, Zhang Liang, Yue Jianbo
City University of Hong Kong Shenzhen Research Institute, Shenzhen, China.
College of Veterinary Medicine, South China Agricultural University, Guangzhou, 510642, China.
BMC Biol. 2024 Jan 25;22(1):12. doi: 10.1186/s12915-024-01819-y.
Many viruses enter host cells by hijacking endosomal trafficking. CapZ, a canonical actin capping protein, participates in endosomal trafficking, yet its precise role in endocytosis and virus infection remains elusive.
Here, we showed that CapZ was transiently associated with early endosomes (EEs) and was subsequently released from the matured EEs after the fusion of two EEs, which was facilitated by PI(3)P to PI(3,5)P2 conversion. Vacuolin-1 (a triazine compound) stabilized CapZ at EEs and thus blocked the transition of EEs to late endosomes (LEs). Likewise, artificially tethering CapZ to EEs via a rapamycin-induced protein-protein interaction system blocked the early-to-late endosome transition. Remarkably, CapZ knockout or artificially tethering CapZ to EEs via rapamycin significantly inhibited flaviviruses, e.g., Zika virus (ZIKV) and dengue virus (DENV), or beta-coronavirus, e.g., murine hepatitis virus (MHV), infection by preventing the escape of RNA genome from endocytic vesicles.
These results indicate that the temporal association of CapZ with EEs facilitates early-to-late endosome transition (physiologically) and the release of the viral genome from endocytic vesicles (pathologically).
许多病毒通过劫持内体运输进入宿主细胞。CapZ是一种典型的肌动蛋白封端蛋白，参与内体运输，但其在胞吞作用和病毒感染中的精确作用仍不清楚。
在这里，我们表明CapZ与早期内体（EEs）短暂相关，随后在两个EEs融合后从成熟的EEs中释放，这一过程由PI(3)P向PI(3,5)P2的转化促进。Vacuolin-1（一种三嗪化合物）使CapZ在EEs处稳定，从而阻止EEs向晚期内体（LEs）的转变。同样，通过雷帕霉素诱导的蛋白质-蛋白质相互作用系统将CapZ人工连接到EEs上也会阻止早期内体向晚期内体的转变。值得注意的是，CapZ基因敲除或通过雷帕霉素将CapZ人工连接到EEs上可通过阻止RNA基因组从内吞小泡中逸出，显著抑制黄病毒，如寨卡病毒（ZIKV）和登革病毒（DENV），或β冠状病毒，如鼠肝炎病毒（MHV）的感染。
这些结果表明，CapZ与EEs的短暂关联促进了早期内体向晚期内体的转变（生理上）以及病毒基因组从内吞小泡中的释放（病理上）。
