Cell reports · 2025
RSK1 reprograms the ubiquitin pathway to promote immune suppression.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Peng Qiao, Chen Yunfei, Zhao Junmiao, Zhu Jiali, Zhuo Huimin, Zheng Yuying, Weng Linjun, Ruiqing He, Tian Enming, Zhang Yiyi, Chen Xianfei, Liu Yuwei, Tan Xiao, Wu Leilei, Tian Hongling, Liu Jingxin, Zhang Jiawen, Zhang Wenhui, Zhang Heping, Zhang Bilong, Shan Zezhi, Zhang Haoyu, Gao Yaohui, Meng Tong, Zhao Linlin, Fang Lin, Shen Bing, Feng Yue, Liu Lei, Yang Hui, Fang Lan, Wang Ping
Аннотация
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.