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A case of convergent evolution: Several viral and bacterial pathogens hijack RSK kinases through a common linear

Frédéric Sorgeloos1, Michael Peeters1,2, Yohei Hayashi1,3

  • 1Virology Unit (VIRO), de Duve Institute, Université Catholique de Louvain, B-1200 Brussels, Belgium.

Proceedings of the National Academy of Sciences of the United States of America
|January 29, 2022
PubMed

Insights

Pathogens like viruses and bacteria convergently evolved to hijack host p90-ribosomal S6-kinases (RSKs). This manipulation inhibits innate immunity by preventing RSK dephosphorylation and blocking stress granule formation.

Area of Science:

  • Microbiology
  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Microbes and hosts engage in long-term coevolutionary relationships.
  • Pathogens exploit host cellular machinery for their own benefit.
  • Mitogen-activated protein kinase (MAPK) pathways are crucial in cellular signaling and host defense.

Purpose of the Study:

  • To investigate the convergent evolution of viral and bacterial pathogens in hijacking host cellular kinases.
  • To elucidate the molecular mechanisms by which pathogens manipulate p90-ribosomal S6-kinases (RSKs).
  • To understand how pathogen-mediated RSK activation impacts innate immunity.

Main Methods:

  • Protein-protein interaction studies to identify binding sites between pathogen proteins and RSKs.
  • Biochemical assays to assess kinase activity and dephosphorylation status.
  • Analysis of pathogen-induced cellular responses, including translation initiation factor inhibition and stress granule formation.

Main Results:

  • Viral and bacterial pathogens have convergently evolved to hijack host RSKs.
  • Theiler's virus L protein, KSHV ORF45, and Yersinia YopM proteins utilize a conserved peptide motif to recruit and activate RSKs.
  • Pathogen-induced RSK activation leads to inhibition of eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2/PKR) and suppression of stress granule formation.
  • Pathogens target a conserved surface-located loop on RSKs, suggesting an allosteric regulation mechanism.

Conclusions:

  • Pathogens have independently evolved similar strategies to manipulate RSKs for their advantage.
  • Hijacking RSKs is a common mechanism employed by diverse pathogens to interfere with innate immunity.
  • This convergent evolution highlights the critical role of RSKs in host defense and pathogen evasion.
Keywords:
host–pathogen interactioninnate immunitypicornavirusshort linear motiftype-3 secretion

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