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Host WD repeat-containing protein 5 inhibits protein kinase R-mediated integrated stress response during measles

Ethan BenDavid1, Chuyuan Yang1, Yuqin Zhou1

  • 1Department of Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, California, USA.

Journal of Virology
|August 28, 2024
PubMed

Insights

Measles virus (MeV) uses the host protein WDR5 to suppress innate immunity. WDR5 is recruited to viral inclusion bodies, enhancing MeV replication by blocking the protein kinase R pathway.

Area of Science:

  • Virology
  • Immunology
  • Molecular Biology

Background:

  • Negative-sense RNA viruses, like measles virus (MeV), form cytoplasmic inclusion bodies (IBs) concentrating viral replication machinery.
  • Understanding virus-host interactions within IBs is crucial for MeV replication and immune evasion.
  • WD repeat-containing protein 5 (WDR5) was previously found to facilitate MeV replication upon translocation to IBs.

Purpose of the Study:

  • To elucidate the mechanism by which WDR5 is recruited to MeV IBs.
  • To investigate the role of WDR5 in MeV replication and host innate immune suppression.
  • To understand how MeV IBs utilize host factors to promote infection.

Main Methods:

  • Investigated the interaction between WDR5 and MeV phosphoprotein using biochemical assays.
  • Analyzed the role of a conserved binding motif on WDR5 in IB recruitment.
  • Assessed the impact of WDR5 on the double-stranded RNA-mediated activation of protein kinase R (PKR) and integrated stress response (ISR).

Main Results:

  • WDR5 is recruited to MeV IBs through complex formation with MeV phosphoprotein.
  • A conserved binding motif on WDR5 mediates its recruitment to IBs.
  • WDR5 suppresses the PKR/ISR pathway, thereby promoting MeV replication.

Conclusions:

  • MeV IBs recruit the host protein WDR5 via interaction with viral phosphoprotein.
  • WDR5's recruitment to IBs enhances MeV replication by inhibiting the host's antiviral PKR/ISR response.
  • This highlights a novel mechanism of viral immune evasion mediated by host-pathogen interactions within IBs.
Keywords:
WD repeat-containing protein 5 (WDR5)inclusion body (IB)integrated stress response (ISR)liquid-liquid phase separation (LLPS)measles virusprotein kinase R (PKR)

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