Rabies virus utilizes neuropilin 2 as an endocytic receptor to trigger TGFBR1-mediated actin polymerization

作者：Ziruo Sun, Jinqiu Wang, Zhiyuan Wen, Lei Shuai, Wenjing Sun, Mengjie Yang, Jinyu Wang, Junyu Chen, Jinying Ge, Weiye Chen, Xijun Wang, Zhigao Bu, Jinliang Wang · 发表于：Journal of Virology · 年份：2025 · DOI：10.1128/jvi.00638-25 · 被引用次数：6 · 研究领域：Toxin Mechanisms and Immunotoxins、Poxvirus research and outbreaks、Rabies epidemiology and control

Rabies virus (RABV), belonging to the rhabdovirus, is a typical large virus that enters cells via clathrin-mediated endocytosis (CME). RABV-containing pits are only partially clathrin-coated and require local actin polymerization for efficient internalization. This unconventional entry process suggests that a specific receptor may be required to initiate actin polymerization during RABV entry. Here, we found that RABV uses the cell membrane protein neuropilin 2 (NRP2) to initiate F-actin polymerization. NRP2 is required for RABV infection and directly interacts with RABV glycoprotein. An antibody against the ectodomain of NRP2 and the soluble ectodomain of NRP2 blocked RABV infection in cells. Expression of human NRP2 in non-susceptible DU145 cells enabled RABV infection. We further found that NRP2 interacted with transforming growth factor-β receptor I (TGFBR1), triggering TGFBR1/2-Cdc42-mediated F-actin polymerization. Vesicular stomatitis virus, another prototypical rhabdovirus, also uses a similar mechanism to enter cells. Our findings demonstrate that NRP2 is a novel receptor for RABV entry by transducing the signal of viral binding across the plasma membrane to initiate actin polymerization. NRP2 may represent one of the long-sought molecules that facilitate large pathogen cell entry via CME.IMPORTANCERabies virus (RABV) enters cells via clathrin-mediated endocytosis (CME), but RABV-containing pits are only partially clathrin-coated, requiring actin polymerization for e...