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Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules
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Methods to Classify Cytoplasmic Foci as Mammalian Stress Granules

Published on: May 12, 2017

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KSHV inhibits stress granule formation by viral ORF57 blocking PKR activation

Nishi R Sharma1, Vladimir Majerciak1, Michael J Kruhlak2

  • 1Tumor Virus RNA Biology Section, RNA Biology Laboratory, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland, United States of America.

Plos Pathogens
|October 31, 2017
PubMed

Insights

Kaposi

Area of Science:

  • Virology
  • Molecular Biology
  • Cellular Biology

Background:

  • Stress granules (SG) are cellular sites for stalled mRNAs and involved in antiviral responses.
  • Kaposi's sarcoma-associated herpesvirus (KSHV) is a human oncogenic virus.
  • KSHV evades host defenses during lytic infection.

Purpose of the Study:

  • To investigate how KSHV overcomes host antiviral responses, specifically SG formation.
  • To identify viral proteins involved in inhibiting SG formation.
  • To elucidate the mechanism by which KSHV ORF57 inhibits SG formation and impacts viral production.

Main Methods:

  • Immunofluorescence analysis of KSHV-infected B lymphocytes.
  • Experimental induction of SG formation using arsenite, poly I:C, and heat stress.
  • Knockdown of protein kinase R (PKR) expression.
  • Analysis of protein-protein interactions (PACT, PKR, ORF57).
  • Assessment of viral gene expression and virion production.

Main Results:

  • KSHV-infected cells are resistant to SG induction.
  • KSHV ORF57 protein inhibits SG formation induced by arsenite and poly I:C, but not heat stress.
  • KSHV ORF37 also inhibits SG formation, while other tested KSHV proteins do not.
  • ORF57 binds PACT and PKR, disrupting the PACT-PKR interaction and inhibiting the PKR/eIF2α pathway.
  • PKR knockdown enhances KSHV virion production.
  • ORF57 inhibits TLR3 phosphorylation induced by poly I:C.
  • HSV-1 ICP27, but not EBV EB2, shares ORF57's ability to block the PKR/eIF2α/SG pathway.

Conclusions:

  • KSHV ORF57 is a key viral protein that inhibits host antiviral stress granule formation.
  • ORF57 targets the PKR/eIF2α signaling pathway to suppress SG assembly.
  • Inhibition of SG formation by ORF57 promotes KSHV lytic replication and viral production.

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