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

  • Nat Commun. 2022 Apr 26;13(1):2256. doi: 10.1038/s41467-022-29948-4.
Lin Zhu   #  1 ,  Ting Gao   #  1 ,  Yi Huang   #  2 ,  Jing Jin  3 ,  Di Wang  3 ,  Leike Zhang  2 ,  Yanwen Jin  1 ,  Ping Li  1 ,  Yong Hu  1 ,  Yan Wu  2 ,  Hainan Liu  1 ,  Qincai Dong  1 ,  Guangfei Wang  1 ,  Tong Zheng  1 ,  Caiwei Song  1 ,  Yu Bai  3 ,  Xun Zhang  3 ,  Yaoning Liu  3 ,  Weihong Yang  3 ,  Ke Xu  4 ,  Gang Zou  5 ,  Lei Zhao  6 ,  Ruiyuan Cao  6 ,  Wu Zhong  6 ,  Xianzhu Xia  7 ,  Gengfu Xiao  8 ,  Xuan Liu  9 ,  Cheng Cao  10
Affiliations
  • 1. Beijing Institute of Biotechnology, Beijing, 100039, China.
  • 2. National Biosafety Laboratory, Chinese Academy of Sciences, Wuhan, Hubei, 430020, China.
  • 3. Institute of Physical Science and Information Technology, Anhui University, Hefei, Anhui, 230601, China.
  • 4. State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China.
  • 5. Insitut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, 200031, China.
  • 6. National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing, 100850, China.
  • 7. Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun, 130000, China.
  • 8. National Biosafety Laboratory, Chinese Academy of Sciences, Wuhan, Hubei, 430020, China. [email protected].
  • 9. Beijing Institute of Biotechnology, Beijing, 100039, China. [email protected].
  • 10. Beijing Institute of Biotechnology, Beijing, 100039, China. [email protected].
  • # Contributed equally.
PMID: 35474062 DOI: 10.1038/s41467-022-29948-4
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.

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