Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer
Activating STING/TBK1 suppresses tumor growth via degrading HPV16/18 E7 oncoproteins in cervical cancer
复制标题
DOI：
10.1038/s41418-023-01242-w
复制
发表时间：
2023-11
影响因子：
12.4
通讯作者：
Xiaodan Huang;Lanqing Huo;Beibei Xiao;Ou Yi;Foping Chen;Junyun Li;Xueping Zheng;Denghui Wei;Yuanzhong Wu;Ruhua Zhang;Xinping Cao;Tiebang Kang;Ying Gao
中科院分区：
文献类型：
--
作者：
Xiaodan Huang;Lanqing Huo;Beibei Xiao;Ou Yi;Foping Chen;Junyun Li;Xueping Zheng;Denghui Wei;Yuanzhong Wu;Ruhua Zhang;Xinping Cao;Tiebang Kang;Ying Gao
宫颈癌是妇科最常见的恶性肿瘤，其病因与人乳头瘤病毒（HPV）的持续感染有关。宿主的先天免疫系统和入侵的HPV都已经发展出复杂而有效的机制来相互抵消。干扰素基因刺激因子（stimulator of interferon genes，STING）作为一种中枢性的先天免疫信号调节因子，在抗病毒和抗肿瘤免疫中发挥着重要作用，而病毒癌蛋白E7，特别是HPV 16/18的E7，在宫颈癌中起着重要作用，并能抑制STING的活性。在本报告中，我们发现STING-TBK 1（TANK结合激酶1）的激活促进E7癌蛋白的遍在蛋白-蛋白酶体降解，以抑制宫颈癌生长。TBK 1能够在Ser 71/Ser 78磷酸化HPV 16/18 E7癌蛋白，促进E3连接酶HUWE 1对E7癌蛋白的泛素化和降解。在功能上，激活的STING通过以TBK 1依赖性方式下调E7癌蛋白来抑制宫颈癌细胞增殖，并可能与辐射协同作用以实现更好的抗肿瘤效果。此外，STING-TBK 1的遗传或免疫激活抑制小鼠宫颈癌的生长，这不依赖于其先天免疫防御。总之，我们的研究结果代表了宿主对肿瘤病毒的先天免疫防御的新层次，并提供了激活STING/TBK 1可能是治疗HPV阳性宫颈癌患者的有希望的策略。
Cervical cancer is the most common gynecologic cancer, etiologically related to persistent infection of human papillomavirus (HPV). Both the host innate immunity system and the invading HPV have developed sophisticated and effective mechanisms to counteract each other. As a central innate immune sensing signaling adaptor, stimulator of interferon genes (STING) plays a pivotal role in antiviral and antitumor immunity, while viral oncoproteins E7, especially from HPV16/18, are responsible for cell proliferation in cervical cancer, and can inhibit the activity of STING as reported. In this report, we find that activation of STING-TBK1 (TANK-binding kinase 1) promotes the ubiquitin-proteasome degradation of E7 oncoproteins to suppress cervical cancer growth. Mechanistically, TBK1 is able to phosphorylate HPV16/18 E7 oncoproteins at Ser71/Ser78, promoting the ubiquitination and degradation of E7 oncoproteins by E3 ligase HUWE1. Functionally, activated STING inhibits cervical cancer cell proliferation via down-regulating E7 oncoproteins in a TBK1-dependent manner and potentially synergizes with radiation to achieve better effects for antitumor. Furthermore, either genetically or pharmacologically activation of STING-TBK1 suppresses cervical cancer growth in mice, which is independent on its innate immune defense. In conclusion, our findings represent a new layer of the host innate immune defense against oncovirus and provide that activating STING/TBK1 could be a promising strategy to treat patients with HPV-positive cervical cancer.