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Bacterial-induced cell fusion is a danger signal triggering cGAS-STING pathway via micronuclei formation

Joanne Wei Kay Ku1, Yahua Chen1, Bryan Jian Wei Lim2

  • 1Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore.

Proceedings of the National Academy of Sciences of the United States of America
|June 24, 2020
PubMed

Insights

Burkholderia pseudomallei uses T6SS5 to fuse host cells, activating the cGAS-STING pathway. This leads to autophagic cell death, not type I IFN production, preventing aberrant cell division.

Area of Science:

  • Microbiology
  • Immunology
  • Cell Biology

Background:

  • Melioidosis, caused by Burkholderia pseudomallei, is a tropical disease with high mortality.
  • The bacterium's type VI secretion system 5 (T6SS5) facilitates host cell fusion for intercellular spread.
  • Host cell fusion is a key mechanism in B. pseudomallei pathogenesis.

Purpose of the Study:

  • To investigate the host cell response to T6SS5-mediated cell fusion.
  • To elucidate the role of the cGAS-STING pathway in this process.
  • To understand the downstream consequences of cGAS-STING activation.

Main Methods:

  • Studying B. pseudomallei-induced host cell fusion in mammalian cells.
  • Analyzing the activation of the cGAS-STING pathway and type I IFN response.
  • Investigating the formation of micronuclei and its correlation with cGAS.
  • Observing outcomes of chemically induced cell fusions.

Main Results:

  • Bacterial T6SS5-dependent cell fusion triggers type I IFN gene expression.
  • The cGAS-STING pathway is activated independently of bacterial ligands, sensing micronuclei formation.
  • cGAS-STING activation leads to autophagic cell death, not type I IFN production.
  • Chemically induced cell fusions mimic these effects.

Conclusions:

  • The cGAS-STING pathway acts as a danger sensor for unnatural cell fusion.
  • Micronuclei formation during cell fusion signals danger to the cGAS-STING pathway.
  • This pathway induces autophagic cell death to limit aberrant cell division and transformation.
Keywords:
DNA damageT6SSautophagycGAS–STINGcell fusion

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