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A20/TNFAIP3 inhibits NF-κB activation induced by the Kaposi's sarcoma-associated herpesvirus vFLIP oncoprotein

S Sakakibara1, G Espigol-Frigole, P Gasperini

  • 1Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Oncogene
|April 25, 2012
PubMed

Insights

Kaposi's sarcoma-associated herpesvirus (KSHV) vFLIP activates NF-κB. A20 protein negatively regulates this activation, impacting KSHV pathogenesis and potentially harmful inflammation in infected cells.

Area of Science:

  • Virology
  • Immunology
  • Cell Biology

Background:

  • Kaposi's sarcoma-associated herpesvirus (KSHV) K13/vFLIP protein drives Kaposi's sarcoma (KS) pathogenesis by activating NF-κB.
  • NF-κB activation leads to pro-inflammatory cytokine transcription, contributing to KS development.

Purpose of the Study:

  • To investigate the role of NF-κB regulatory proteins A20, ABIN-1, and ABIN-3 in KSHV vFLIP-induced NF-κB activation.
  • To determine how A20 modulates NF-κB signaling and its functional consequences in KSHV-infected cells.

Main Methods:

  • Reporter assays to assess NF-κB activation by vFLIP and A20 in 293T cells.
  • Mutational analysis of A20 to identify critical domains for NF-κB modulation.
  • Functional assays to evaluate A20's effect on vFLIP-induced gene expression, cell proliferation, and protein levels.

Main Results:

  • KSHV vFLIP induces A20, ABIN-1, and ABIN-3 expression in endothelial cells; A20 is present in KS spindle cells.
  • A20 significantly impairs vFLIP-induced NF-κB activation, while ABIN-1 and ABIN-3 do not.
  • A20's C-terminal domain (residues 427-790) is crucial for NF-κB modulation, not the OTU domain.
  • A20 inhibits vFLIP-induced IP-10 chemokine expression, reduces cell proliferation, and increases IKK1 levels.

Conclusions:

  • A20 acts as a negative regulator of KSHV vFLIP-induced NF-κB activation.
  • A20 mitigates excessive NF-κB signaling, potentially protecting KSHV-infected cells.
  • A20 plays a significant role in the pathogenesis of KSHV-associated diseases where vFLIP is expressed.

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