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Recognition of phylogenetically diverse pathogens through enzymatically amplified recruitment of RNF213

Ana Crespillo-Casado1, Prathyush Pothukuchi1, Katerina Naydenova1

  • 1MRC Laboratory of Molecular Biology, Division of Protein and Nucleic Acid Chemistry, Francis Crick Avenue, Cambridge, CB2 0QH, UK.

EMBO Reports
|October 7, 2024
PubMed

Insights

The E3 ubiquitin ligase RNF213 binds diverse pathogens by forming protective coats. This process involves ATP hydrolysis and cooperative recruitment, crucial for innate immunity against various microbes.

Area of Science:

  • Immunology
  • Molecular Biology
  • Structural Biology

Background:

  • Innate immunity recognizes pathogen-associated molecular patterns (PAMPs) for pathogen detection.
  • PAMPs are typically taxa-specific, allowing pattern recognition receptors to distinguish between different microbes.
  • The broad-spectrum pathogen recognition mechanism of E3 ubiquitin ligase RNF213 was previously unknown.

Purpose of the Study:

  • To investigate how RNF213 recognizes and responds to phylogenetically distant pathogens.
  • To elucidate the structural and functional mechanisms underlying RNF213's broad pathogen recognition capabilities.

Main Methods:

  • Cryo-electron microscopy (cryo-EM) to resolve the structure of RNF213's CBM20 domain.
  • Biochemical assays to assess the role of ATP hydrolysis and E3 ligase activity.
  • In vitro studies to analyze RNF213 coat formation on different pathogens.

Main Results:

  • RNF213's evolutionary history suggests adaptation to diverse pathogen structures, particularly within its CBM20 domain.
  • RNF213 forms coats on Gram-negative bacteria (Salmonella), Gram-positive bacteria (Listeria), and eukaryotes (Toxoplasma).
  • ATP hydrolysis and RZ finger-mediated E3 ligase activity are essential for RNF213 coat formation and function.
  • Coat formation is a cooperative process initiated by rate-limiting events, not simple diffusion.

Conclusions:

  • RNF213 employs a unique mechanism of enzymatically amplified cooperative recruitment to respond to evolutionarily distant pathogens.
  • This mechanism allows RNF213 to provide broad innate immune defense against a wide range of microbial threats.
Keywords:
Host-pathogen InteractionInnate ImmunityPattern Recognition ReceptorPositive SelectionUbiquitylation

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