TY - JOUR
T1 - Deleting key autophagy elongation proteins induces acquirement of tumor-associated phenotypes via ISG15
AU - Kong, Eun Bin
AU - Kim, Hag Dong
AU - Kim, Joon
N1 - Funding Information:
Acknowledgements This work was supported by NRF-2017R1E1A1A01074101, NRF-2019S1A5A2A03050121, and Korea University grant.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2020/8/1
Y1 - 2020/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85081593035&partnerID=8YFLogxK
U2 - 10.1038/s41418-020-0519-y
DO - 10.1038/s41418-020-0519-y
M3 - Article
C2 - 32127658
AN - SCOPUS:85081593035
VL - 27
SP - 2517
EP - 2530
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 8
ER -