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Activation of PKR by RNA misfolding: HDV ribozyme dimers activate PKR

Laurie A Heinicke1, Philip C Bevilacqua

  • 1Department of Chemistry, Center for RNA Molecular Biology, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.

RNA (New York, N.Y.)
|October 30, 2012
PubMed

Insights

Misfolded RNA dimers, not long dsRNA, activate Protein Kinase R (PKR) in innate immunity. Shortening a specific RNA region enhanced this activation, revealing a new mechanism for immune response regulation.

Area of Science:

  • Molecular Biology
  • Immunology
  • RNA Biology

Background:

  • Protein Kinase R (PKR) is a key mediator of innate immunity activated by double-stranded RNA (dsRNA).
  • PKR activation typically requires long dsRNA stretches or specific RNA structures like pseudoknots.
  • Regulation of PKR by globular RNA structures remained largely unexplored.

Purpose of the Study:

  • To investigate the Hepatitis Delta Virus (HDV) ribozyme, a model globular RNA, as a potential PKR activator.
  • To elucidate the structural basis of RNA-mediated PKR activation.
  • To explore the role of RNA misfolding in innate immune response.

Main Methods:

  • Utilized HDV ribozyme variants with modified P4 pairing regions.
  • Assessed PKR activation by different HDV ribozyme constructs.
  • Employed native gel electrophoresis and enzymatic structure mapping to analyze RNA structures.

Main Results:

  • The HDV ribozyme sequence alone activated PKR.
  • A variant with a shortened P4 region exhibited the most potent PKR activation.
  • Misfolded HDV ribozyme dimers were identified as the species responsible for PKR activation.
  • Shortened P4 regions were shown to enhance RNA dimer formation.

Conclusions:

  • RNA misfolding, specifically in dimers of the HDV ribozyme, can activate PKR.
  • The P4 region's length influences RNA dimer formation and subsequent PKR activation.
  • These findings reveal a novel pathway linking RNA structure and innate immunity, with potential implications for human diseases.

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