Abstract
Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. RABV enters cells via clathrin-mediated endocytosis upon receptor binding. The detailed mechanism of this process and how it is regulated are not fully understood. Here, we carried out a high-through-put RNAi analysis and identified AP2-associated kinase 1 (AAK1), a serine/threonine kinase, as an important cellular component in regulating the entry of RABV. AAK1 knock-down greatly inhibits RABV infection of cells, and AAK1-induced phosphorylation of threonine 156 of the μ subunit of adaptor protein 2 (AP2M1) is found to be required for RABV entry. Inhibition of AAK1 kinase activity by sunitinib blocked AP2M1 phosphorylation, significantly inhibiting RABV infection and preventing RABV from entering early endosomes. In vivo studies revealed that sunitinib prolongs the survival of mice challenged with RABV street virus. Our findings indicate that AAK1 is a potential drug target for postexposure prophylaxis against rabies.
Highlights
Rabies is a fatal zoonotic disease that leads to nearly 60,000 deaths annually worldwide [1].It is caused by the rabies virus (RABV), which is highly neurotropic
We found that downregulation of associated kinase 1 (AAK1) mRNA significantly inhibited RABV
A growth kinetic assay with recombinant RABV ERA-mCherry showed that the AAK1 knock-down inhibited RABV infection in HEK293 cells post-transfection (Figure 1C)
Summary
Chong Wang 1,† , Jinliang Wang 1,† , Lei Shuai 1 , Xiao Ma 1 , Hailin Zhang 1 , Renqiang Liu 1 , Weiye Chen 1 , Xijun Wang 1 , Jinying Ge 1 , Zhiyuan Wen 1, * and Zhigao Bu 1,2, *. Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonoses, Yangzhou University, Yangzhou 225009, China. Received: 15 November 2019; Accepted: 24 December 2019; Published: 30 December 2019
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