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<p>The RIG-I/MAVS signaling stimulates anti-tumor immunity by triggering the production of inflammatory cytokines. Activation of MAVS induced by viral RNA and RIG-I binding is critical in this pathway. However, the molecular mechanism underlying the regulation of MAVS activity and its function in anti-tumor immunity is not fully understood. Here, we report that the ubiquitin-specific protease 35 (USP35) negatively regulates the MAVS signaling. Mechanistically, USP35 interacts with MAVS and removes its K63-linked polyubiquitin chains, thereby inhibiting viral-induced MAVS-TBK1-IRF3 activation and downstream inflammatory gene expression. Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells. Thus, our study identifies USP35 as a negative regulator of MAVS signaling, representing a potential immunosuppressive factor in cutaneous melanoma.</p>

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Deubiquitination enzyme USP35 negatively regulates MAVS signaling to inhibit anti-tumor immunity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月27日

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  • Heping Zhang,
  • Jiali Zhu,
  • Rong He,
  • Lin Xu,
  • Yunfei Chen,
  • Haihong Yu,
  • Xuejiao Sun,
  • Shengpeng Wan,
  • Xiaolan Yin,
  • Yu’e Liu,
  • Jie Gao,
  • Yue Li,
  • Zhixiong Li,
  • Yi Lu,
  • Qing Xu

摘要

The RIG-I/MAVS signaling stimulates anti-tumor immunity by triggering the production of inflammatory cytokines. Activation of MAVS induced by viral RNA and RIG-I binding is critical in this pathway. However, the molecular mechanism underlying the regulation of MAVS activity and its function in anti-tumor immunity is not fully understood. Here, we report that the ubiquitin-specific protease 35 (USP35) negatively regulates the MAVS signaling. Mechanistically, USP35 interacts with MAVS and removes its K63-linked polyubiquitin chains, thereby inhibiting viral-induced MAVS-TBK1-IRF3 activation and downstream inflammatory gene expression. Importantly, depletion of USP35 significantly enhances the anti-tumor immunity and synergizes with oncolytic virotherapy to suppress xenograft tumor growth of melanoma cells. Thus, our study identifies USP35 as a negative regulator of MAVS signaling, representing a potential immunosuppressive factor in cutaneous melanoma.