RSK1 reprograms the ubiquitin pathway to promote immune suppression

  • Cell Rep. 2025 Sep 22;44(10):116323. doi: 10.1016/j.celrep.2025.116323.
Qiao Peng  1 ,  Yunfei Chen  2 ,  Junmiao Zhao  1 ,  Jiali Zhu  1 ,  Huimin Zhuo  1 ,  Yuying Zheng  1 ,  Linjun Weng  1 ,  Ruiqing He  1 ,  Enming Tian  1 ,  Yiyi Zhang  1 ,  Xianfei Chen  1 ,  Yuwei Liu  1 ,  Xiao Tan  1 ,  Leilei Wu  1 ,  Hongling Tian  1 ,  Jingxin Liu  1 ,  Jiawen Zhang  3 ,  Wenhui Zhang  1 ,  Heping Zhang  1 ,  Bilong Zhang  4 ,  Zezhi Shan  1 ,  Haoyu Zhang  1 ,  Yaohui Gao  1 ,  Tong Meng  3 ,  Linlin Zhao  1 ,  Lin Fang  1 ,  Bing Shen  1 ,  Yue Feng  5 ,  Lei Liu  6 ,  Hui Yang  6 ,  Lan Fang  7 ,  Ping Wang  8
Affiliations
  • 1. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Shanghai 200072, China.
  • 2. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Shanghai 200072, China; Clinical Center for Brain and Spinal Cord Research, Affiliated Shanghai Blue Cross Brain Hospital, School of Medicine, Shanghai 200072, China.
  • 3. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Shanghai 200072, China; Shanghai General Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai 200940, China.
  • 4. Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China.
  • 5. State Key Laboratory of Chemical Resource Engineering, Beijing Advanced Innovation Center for Soft Matter Science and Engineering, College of Life Science and Technology, Beijing University of Chemical Technology, Beijing, China.
  • 6. Tsinghua-Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • 7. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Shanghai 200072, China. Electronic address: [email protected].
  • 8. Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Shanghai 200072, China; Clinical Center for Brain and Spinal Cord Research, Affiliated Shanghai Blue Cross Brain Hospital, School of Medicine, Shanghai 200072, China. Electronic address: [email protected].
PMID: 40986423 DOI: 10.1016/j.celrep.2025.116323
Abstract

Although immune checkpoint blockade (ICB) is an effective therapeutic strategy, tumor intrinsic resistance to ICB limits its benefits for a majority of Cancer patients. Via multiple in vivo screens, we identified RNF19A as an immune suppressor. RNF19A suppresses ICB efficacy by ubiquitinating cGAS to inhibit the release of type I interferon. Surprisingly, UBE2L6, originally identified as a critical interferon-induced ISG15-conjugating E2 enzyme for ISGylation, functions as the major ubiquitin-conjugating E2 enzyme to enable RNF19A-driven cGAS ubiquitination. Further, RSK1 phosphorylates UBE2L6 to switch its substrate from ISG15 to ubiquitin, thus converting it from an immune response enhancer to a suppressor. In xenograft models, targeting RSK1 or blocking UBE2L6 phosphorylation improves immune response. In patient tissues, the levels of UBE2L6 and its phosphorylation correlate with poor immune infiltration, limited immune and radiation therapy response, and prognosis. Taken together, we demonstrate that RSK1-mediated UBE2L6 phosphorylation and UBE2L6-RNF19A-driven cGAS ubiquitination lead to tumor-intrinsic immune suppression.

Keywords
CP: Immunology; CRISPR-Cas9 screen; immune suppression; phosphorylation; ubiquitination.
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