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A conserved domain in the leader proteinase of foot-and-mouth disease virus is required for proper subcellular

Teresa de los Santos1, Fayna Diaz-San Segundo, James Zhu

  • 1Plum Island Animal Disease Center, U.S. Department of Agriculture, Greenport, New York 11944, USA. teresa.delossantos@ars.usda.gov

Journal of Virology
|December 5, 2008
PubMed

Insights

Mutating the SAP domain of foot-and-mouth disease virus leader proteinase (L(pro)) attenuates viral replication. This mutation prevents L(pro) from degrading the NF-kappaB p65/RelA subunit, preserving innate immune responses.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Foot-and-mouth disease virus (FMDV) leader proteinase (L(pro)) antagonizes innate immunity by inhibiting interferon (IFN) production.
  • L(pro) blocks host mRNA translation and degrades the NF-kappaB p65/RelA subunit.

Purpose of the Study:

  • To investigate the role of the SAP domain within FMDV L(pro) in viral pathogenesis.
  • To determine if mutations in the SAP domain affect L(pro)'s interaction with NF-kappaB and innate immune signaling.

Main Methods:

  • Site-directed mutagenesis was used to create single and double mutants within the L(pro) SAP domain.
  • Mutant viruses were analyzed for replication efficiency, L(pro) subcellular localization, p65/RelA degradation, and NF-kappaB transcriptional activity.

Main Results:

  • A double mutant virus exhibited an attenuated phenotype in cell culture.
  • The double mutant L(pro) showed altered subcellular distribution and failed to degrade p65/RelA.
  • NF-kappaB-dependent transcription remained active in cells infected with the double mutant virus, unlike WT FMDV infection.
  • Degradation of the translation factor eIF-4G was unaffected by the SAP domain mutations.

Conclusions:

  • Mutation of the FMDV L(pro) SAP domain separates its functions, specifically preventing p65/RelA degradation while maintaining translational shutoff.
  • This finding highlights a novel mechanism by which FMDV L(pro) modulates the host immune response and suggests potential therapeutic targets.

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