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

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.

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Publication Details

Journal
Cell Death and Disease
Published
2025-02-27
DOI
https://doi.org/10.1038/s41419-025-07411-8
Citations
2
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
1.59

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article

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

Jie Gao, Xiaolan Yin, Rong He, Xuejiao Sun et al.
2 citations
Cell Death and Disease
interferon and immune responses
1.59
article

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

Jie Gao, Xiaolan Yin, Rong He, Xuejiao Sun, Yunfei Chen, Yue Li, Lin Xu, Haihong Yu, Yi Lu, Jiali Zhu, Qing Xu, Zhixiong Li, Heping Zhang, Shengpeng Wan
article en
2 citations

Abstract

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.

Cell Death and DiseaseVol. 16(1)
Tongji University (CN), Technology Holding (United States) (US), Shanghai East Hospital (CN), Shanghai Tenth People's Hospital (CN), Tongji Hospital (CN)
National Natural Science Foundation of China, Natural Science Foundation of Jiangxi Province
Good health and well-being
Openalex Percentile: Top 19%
interferon and immune responses
1.59
DOIOpen Access PDFOpenAlex
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