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<p>The cGAS-STING pathway plays a central role in controlling tumor progression through nucleic acid sensing and type I Interferon production. Here, we identify Poly(rC) Binding Protein 1 as a tumor suppressor that amplifies cGAS-STING signaling in breast cancer. Using patient datasets and a transgenic mouse model with conditional PCBP1 knockout in mammary epithelial cells, we show that PCBP1 expression correlates with improved survival, reduced tumor burden, increased type I Interferon and Interferon Stimulated Gene expression, and elevated cytotoxic T cell infiltration. Mechanistically, PCBP1 binds cytosine-rich single-stranded motifs via its KH domains and increases cGAS affinity to these nucleic acids. Mutation of PCBP1’s conserved GXXG loops impairs nucleic acid binding and cGAS activation. Although cGAS is a double-stranded DNA sensor with no intrinsic sequence specificity, we uncover that the single-stranded nucleic-acid binding protein PCBP1 enhances cGAS sensing by engaging sequence-specific motifs, acting as a nucleic acid co-sensor that impairs tumorigenesis.</p>

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PCBP1 binding to single-stranded poly-cytosine motifs enhances cGAS sensing and impairs breast cancer development

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月7日

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  • Cécile Fréreux,
  • Joseph A. Q. Karam,
  • Breege V. Howley,
  • Bryan Granger,
  • Paramita Chakraborty,
  • Silvia Vaena,
  • Martin Romeo,
  • Annamarie C. Dalton,
  • Bidyut K. Mohanty,
  • Shikhar Mehrotra,
  • Philip H. Howe

摘要

The cGAS-STING pathway plays a central role in controlling tumor progression through nucleic acid sensing and type I Interferon production. Here, we identify Poly(rC) Binding Protein 1 as a tumor suppressor that amplifies cGAS-STING signaling in breast cancer. Using patient datasets and a transgenic mouse model with conditional PCBP1 knockout in mammary epithelial cells, we show that PCBP1 expression correlates with improved survival, reduced tumor burden, increased type I Interferon and Interferon Stimulated Gene expression, and elevated cytotoxic T cell infiltration. Mechanistically, PCBP1 binds cytosine-rich single-stranded motifs via its KH domains and increases cGAS affinity to these nucleic acids. Mutation of PCBP1’s conserved GXXG loops impairs nucleic acid binding and cGAS activation. Although cGAS is a double-stranded DNA sensor with no intrinsic sequence specificity, we uncover that the single-stranded nucleic-acid binding protein PCBP1 enhances cGAS sensing by engaging sequence-specific motifs, acting as a nucleic acid co-sensor that impairs tumorigenesis.