Ebola virus VP35 hijacks the PKA-CREB1 pathway for replication and pathogenesis by AKIP1 association

Lin Zhu, Ting Gao, Yi Huang, Jing Jin, Di Wang, Leike Zhang, Yanwen Jin, Ping Li, Yong Hu, Yan Wu, Hainan Liu, Qincai Dong, Guangfei Wang, Tong Zheng, Caiwei Song, Yu Bai, Xun Zhang, Yaoning Liu, Weihong Yang, Ke Xu, Gang Zou, Lei Zhao, Ruiyuan Cao, Wu Zhong, Xianzhu Xia, Gengfu Xiao (), Xuan Liu () and Cheng Cao ()
Additional contact information
Lin Zhu: Beijing Institute of Biotechnology
Ting Gao: Beijing Institute of Biotechnology
Yi Huang: National Biosafety Laboratory, Chinese Academy of Sciences
Jing Jin: Anhui University
Di Wang: Anhui University
Leike Zhang: National Biosafety Laboratory, Chinese Academy of Sciences
Yanwen Jin: Beijing Institute of Biotechnology
Ping Li: Beijing Institute of Biotechnology
Yong Hu: Beijing Institute of Biotechnology
Yan Wu: National Biosafety Laboratory, Chinese Academy of Sciences
Hainan Liu: Beijing Institute of Biotechnology
Qincai Dong: Beijing Institute of Biotechnology
Guangfei Wang: Beijing Institute of Biotechnology
Tong Zheng: Beijing Institute of Biotechnology
Caiwei Song: Beijing Institute of Biotechnology
Yu Bai: Anhui University
Xun Zhang: Anhui University
Yaoning Liu: Anhui University
Weihong Yang: Anhui University
Ke Xu: Wuhan University
Gang Zou: Insitut Pasteur of Shanghai, Chinese Academy of Sciences
Lei Zhao: Beijing Institute of Pharmacology and Toxicology
Ruiyuan Cao: Beijing Institute of Pharmacology and Toxicology
Wu Zhong: Beijing Institute of Pharmacology and Toxicology
Xianzhu Xia: Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences
Gengfu Xiao: National Biosafety Laboratory, Chinese Academy of Sciences
Xuan Liu: Beijing Institute of Biotechnology
Cheng Cao: Beijing Institute of Biotechnology

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract Ebola virus (EBOV), one of the deadliest viruses, is the cause of fatal Ebola virus disease (EVD). The underlying mechanism of viral replication and EBOV-related hemorrhage is not fully understood. Here, we show that EBOV VP35, a cofactor of viral RNA-dependent RNA polymerase, binds human A kinase interacting protein (AKIP1), which consequently activates protein kinase A (PKA) and the PKA-downstream transcription factor CREB1. During EBOV infection, CREB1 is recruited into EBOV ribonucleoprotein complexes in viral inclusion bodies (VIBs) and employed for viral replication. AKIP1 depletion or PKA-CREB1 inhibition dramatically impairs EBOV replication. Meanwhile, the transcription of several coagulation-related genes, including THBD and SERPINB2, is substantially upregulated by VP35-dependent CREB1 activation, which may contribute to EBOV-related hemorrhage. The finding that EBOV VP35 hijacks the host PKA-CREB1 signal axis for viral replication and pathogenesis provides novel potential therapeutic approaches against EVD.

Date: 2022
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DOI: 10.1038/s41467-022-29948-4

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