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.

中文翻译：

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删除关键的自噬延伸蛋白可通过 ISG15 诱导获得肿瘤相关表型。

自噬是一种细胞分解代谢过程，它使用溶酶体降解系统维持细胞内稳态。我们证明通过消耗必需的自噬延伸蛋白 Atg5 或 Atg7 来抑制自噬，通过 STING 介导的胞质 dsDNA 反应诱导 ISG15 表达。基因组稳定性在 ATG5 或 ATG7 耗尽的细胞中受损，因此，DNA 的双链断裂增加和细胞溶质 dsDNA 积累。积累的胞质 dsDNA 诱导 STING 通路激活 I 型 IFN 信号，从而诱导 STAT1 活性并下调 ATF3。当 ATG5 或 ATG7 的消耗抑制自噬时，ATF3 下调而 STAT1 上调。此外，抑制自噬通过 STAT1 激活诱导 ISG15 表达，从而促进肿瘤相关表型的获得，如迁移、侵袭、和扩散。总之，似乎通过 STING 介导的胞质 dsDNA 反应，STAT1-ISG15 轴介导了自噬和免疫系统之间与肿瘤进展相关的关系。此外，结合自噬控制，调节 ISG15 表达可能是癌症免疫治疗的新策略。