Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China; College of Pharmacy, Jinan University, Guangzhou 510632, China.
Biomedicine Research and Development Center, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou 510632, China.
Virology. 2014 Jan 20;449:88-95. doi: 10.1016/j.virol.2013.11.011. Epub 2013 Nov 26.
Actin and its regulators are critical for neuronal function. Infection with herpes simplex virus 1 (HSV-1) remodels neuronal cell actin dynamics, which may relate virus-induced pathological processes in the nervous system. We previously demonstrated that cofilin is an actin regulator that participates in HSV-1-induced actin dynamics in neuronal cells, but how HSV-1 regulates cofilin has remained unclear. In the present study, we demonstrated the HSV-1-induced the inactivation of cofilin and the accumulation of phosphorylated cofilin in the nucleus, which together benefited viral replication. This consistent cofilin inactivation was achieved by the downregulation of slingshot 1 (SSH1). Notably, virus-induced SSH1 downregulation depended on the ubiquitin-proteasome system. Cofilin inactivation is therefore critical for HSV-1 replication during neuronal infection and is maintained by SSH1 downregulation. Moreover, these results provide new insight into the HSV-1-induced neurological pathogenesis and suggest potential new strategies to inhibit HSV-1 replication.
肌动蛋白及其调节因子对于神经元功能至关重要。单纯疱疹病毒 1（HSV-1）的感染会重塑神经元细胞中的肌动蛋白动力学，这可能与病毒在神经系统中引起的病理过程有关。我们之前的研究表明，丝切蛋白是一种参与神经元细胞中 HSV-1 诱导的肌动蛋白动力学的肌动蛋白调节因子，但 HSV-1 如何调节丝切蛋白仍不清楚。在本研究中，我们证明了 HSV-1 诱导了丝切蛋白的失活和磷酸化丝切蛋白在核内的积累，这两者共同有利于病毒的复制。这种一致的丝切蛋白失活是通过下调 slingShot1（SSH1）实现的。值得注意的是，病毒诱导的 SSH1 下调依赖于泛素-蛋白酶体系统。因此，丝切蛋白失活对于神经元感染期间的 HSV-1 复制至关重要，并且通过 SSH1 下调来维持。此外，这些结果为 HSV-1 诱导的神经发病机制提供了新的见解，并为抑制 HSV-1 复制提供了新的策略。
