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The Serine/Threonine Kinase AP2-Associated Kinase 1 Plays an Important Role in Rabies Virus Entry

Chong Wang1, Jinliang Wang1, Lei Shuai1

  • 1State Key Laboratory of Veterinary Biotechnology, Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin 150069, China.

Viruses
|January 8, 2020
PubMed

Insights

AP2-associated kinase 1 (AAK1) regulates rabies virus entry into cells. Inhibiting AAK1 with sunitinib blocks viral infection and improves survival in mice, suggesting AAK1 as a potential drug target for rabies.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Rabies virus (RABV) is a neurotropic virus that causes fatal encephalitis in humans.
  • RABV entry into host cells occurs via clathrin-mediated endocytosis, but regulatory mechanisms remain unclear.
  • Understanding RABV cellular entry is crucial for developing effective antiviral therapies.

Purpose of the Study:

  • To identify cellular factors regulating RABV entry.
  • To investigate the role of AP2-associated kinase 1 (AAK1) in RABV infection.
  • To evaluate AAK1 as a potential therapeutic target for rabies.

Main Methods:

  • High-throughput RNA interference (RNAi) screening to identify host factors involved in RABV entry.
  • Cell-based assays to assess RABV infection and viral entry.
  • Biochemical analysis of protein phosphorylation, including AAK1 and AP2M1.
  • In vivo studies using a mouse model of rabies.

Main Results:

  • AAK1 was identified as a key cellular kinase regulating RABV entry.
  • AAK1 knockdown significantly inhibited RABV infection.
  • AAK1 phosphorylates threonine 156 of AP2M1, a step essential for RABV entry.
  • The kinase inhibitor sunitinib blocked AAK1 activity, inhibited viral entry, and prolonged survival in a mouse model.

Conclusions:

  • AAK1 plays a critical role in regulating RABV cellular entry.
  • AAK1-mediated phosphorylation of AP2M1 is essential for RABV infection.
  • AAK1 represents a promising therapeutic target for post-exposure prophylaxis against rabies.
Keywords:
AAK1AP2M1rabiessunitinib

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