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ASFV pD345L protein negatively regulates NF-κB signalling by inhibiting IKK kinase activity

Huan Chen1, Zhenzhong Wang1,2, Xiaoyu Gao1

  • 1MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu, China.

Veterinary Research
|April 24, 2022
PubMed

Insights

African swine fever virus (ASFV) protein pD345L inhibits the cGAS/STING pathway by blocking IKKα/β kinase activity. This viral protein disrupts innate immune responses, aiding ASFV infection.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • The NF-κB pathway is crucial for antiviral defense against viruses like African swine fever virus (ASFV).
  • ASFV possesses numerous proteins that can evade host innate immune responses, with many viral proteins remaining uncharacterized.

Purpose of the Study:

  • To identify novel ASFV proteins involved in subverting host antiviral signaling.
  • To elucidate the mechanism by which ASFV protein pD345L interferes with the cGAS/STING-mediated NF-κB pathway.

Main Methods:

  • Overexpression of ASFV pD345L in cells.
  • Analysis of IFNβ and NF-κB activation using reporter assays.
  • Western blotting to assess protein interactions and phosphorylation.
  • Site-directed mutagenesis to investigate the role of exonuclease activity.

Main Results:

  • ASFV pD345L suppresses cGAS/STING-induced IFNβ and NF-κB activation.
  • pD345L inhibits IκB kinase (IKKα/β) activity, acting downstream of IKK and upstream of p65.
  • pD345L directly binds to IKKα and IKKβ, disrupting their kinase function.
  • The inhibitory effect of pD345L on NF-κB signaling is independent of its exonuclease activity.

Conclusions:

  • ASFV protein pD345L is a novel inhibitor of cGAS/STING-mediated NF-κB signaling.
  • pD345L blocks IKKα/β kinase activity through protein-protein interactions, thereby dampening the innate immune response.
  • This viral mechanism contributes to ASFV's ability to evade host defenses.
Keywords:
African swine fever virusIKK complexNF-κBkinase activitypD345L

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