Deleting key autophagy elongation proteins induces acquirement of tumor-associated phenotypes via ISG15.

Cell Death and Differentiation
EunBin KongJoon Kim

Abstract

Autophagy is a cellular catabolic process that maintains intracellular homeostasis using lysosomal degradation systems. We demonstrate that inhibiting autophagy by depleting essential autophagy elongation proteins, Atg5 or Atg7, induces ISG15 expression through STING-mediated cytosolic dsDNA response. Genome stability is impaired in ATG5- or ATG7-depleted cells, and thus, double-strand breakages of DNA increase and cytosolic dsDNA accumulates. Accumulated cytosolic dsDNA induces the STING pathway to activate type I IFN signals which induce STAT1 activity and downregulate ATF3. When depletion of ATG5 or ATG7 inhibits autophagy, ATF3 is downregulated and STAT1 is upregulated. Furthermore, inhibiting autophagy induces ISG15 expression through STAT1 activation, which promotes acquisition of tumor-associated phenotypes such as migration, invasion, and proliferation. In conclusion, it appears that via the STING-mediated cytosolic dsDNA response, the STAT1-ISG15 axis mediates the relationship between autophagy and the immune system in relation to tumor progression. Moreover, combined with autophagy control, regulating ISG15 expression could be a novel strategy for cancer immunotherapy.

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Citations

Aug 4, 2020·Molecular Oncology·Chelsea Gerada, Kevin M Ryan
Aug 6, 2021·Biology Direct·Eleonora MammarellaIvano Amelio
Aug 7, 2021·Cell Death & Disease·David Della-MorteNicola Di Daniele

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Methods Mentioned

BETA
RNAseq
PCR
transfection
chemical treatments
xenograft

Software Mentioned

OpenComet
nedxseq500
imagej
Fiji

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