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<p>Mitochondrial DNA (mtDNA) serves as a potent activator for cellular innate immune responses. Topoisomerase 3α (TOP3α), a type IA topoisomerase, is canonically localized to mitochondria and nuclei, but its enigmatic cytosolic fraction—observed over two decades ago—has remained functionally undefined. Here, we uncover a critical role for cytosolic TOP3α in amplifying mtDNA-triggered innate immunity. We observe that aberrant TOP3α expression causes mtDNA clustering and release via mPTP-VDAC, stimulating cGAS-mediated inflammatory responses. Cytosolic TOP3α facilitates the sensing of released mtDNA by cGAS and amplifies downstream innate immune signaling. Using an in vitro cell-free system, we reveal that TOP3α directly augments mtDNA interaction with cGAS, which in turn competes with TOP3α for mtDNA binding. A rare mutation of a highly conserved residue (G250D) of TOP3α impairs the assembly of TOP3α polypeptides into protein complexes and its binding to mtDNA. Furthermore, mutant TOP3α hinders cGAS-mtDNA interaction and compromises cGAS-driven immunity. Our findings reveal a function for cytosolic TOP3α as a regulator for cGAS-driven inflammation.</p>

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Cytosolic TOP3α facilitates mitochondrial DNA sensing by cGAS

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月30日

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  • Dongjing Cai,
  • Cheng Chen,
  • Piyanat Meekrathok,
  • Weiqian Zeng,
  • Zheng Wang,
  • Zhigang Peng,
  • Yunan Mo,
  • Xia Xu,
  • Junling Wang,
  • Jian Qiu

摘要

Mitochondrial DNA (mtDNA) serves as a potent activator for cellular innate immune responses. Topoisomerase 3α (TOP3α), a type IA topoisomerase, is canonically localized to mitochondria and nuclei, but its enigmatic cytosolic fraction—observed over two decades ago—has remained functionally undefined. Here, we uncover a critical role for cytosolic TOP3α in amplifying mtDNA-triggered innate immunity. We observe that aberrant TOP3α expression causes mtDNA clustering and release via mPTP-VDAC, stimulating cGAS-mediated inflammatory responses. Cytosolic TOP3α facilitates the sensing of released mtDNA by cGAS and amplifies downstream innate immune signaling. Using an in vitro cell-free system, we reveal that TOP3α directly augments mtDNA interaction with cGAS, which in turn competes with TOP3α for mtDNA binding. A rare mutation of a highly conserved residue (G250D) of TOP3α impairs the assembly of TOP3α polypeptides into protein complexes and its binding to mtDNA. Furthermore, mutant TOP3α hinders cGAS-mtDNA interaction and compromises cGAS-driven immunity. Our findings reveal a function for cytosolic TOP3α as a regulator for cGAS-driven inflammation.