热应激时，mA 修饰通过反向调节 HPV E7 癌蛋白的阅读蛋白 IGF2BP1，赋予 HPV E7 癌转录本对热的敏感性。

mA modification confers thermal vulnerability to HPV E7 oncotranscripts via reverse regulation of its reader protein IGF2BP1 upon heat stress.

机构信息

Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China; Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

Women's Hospital, Institute of Genetics, and Department of Environmental Medicine, Zhejiang University School of Medicine, Hangzhou 310006, China.

出版信息

Cell Rep. 2022 Oct 25;41(4):111546. doi: 10.1016/j.celrep.2022.111546.

DOI:10.1016/j.celrep.2022.111546

PMID:36288717

Abstract

Human papillomavirus (HPV)-induced carcinogenesis critically depends on the viral early protein 7 (E7), making E7 an attractive therapeutic target. Here, we report that the E7 messenger RNA (mRNA)-containing oncotranscript complex can be selectively targeted by heat treatment. In HPV-infected cells, viral E7 mRNA is modified by N-methyladenosine (mA) and stabilized by IGF2BP1, a cellular mA reader. Heat treatment downregulates E7 mRNA and protein by destabilizing IGF2BP1 without the involvement of canonical heat-shock proteins and reverses HPV-associated carcinogenesis in vitro and in vivo. Mechanistically, heat treatment promotes IGF2BP1 aggregation only in the presence of mA-modified E7 mRNA to form distinct heat-induced mA E7 mRNA-IGF2BP1 granules, which are resolved by the ubiquitin-proteasome system. Collectively, our results not only show a mutual regulation between mA RNA and its reader but also provide a heat-treatment-based therapeutic strategy for HPV-associated malignancies by specifically downregulating E7 mRNA-IGF2BP1 oncogenic complex.

摘要

人乳头瘤病毒（HPV）诱导的癌变过程在很大程度上依赖于病毒早期蛋白 7（E7），这使得 E7 成为一个有吸引力的治疗靶点。在这里，我们报告说，含有 E7 mRNA 的致癌转录本复合物可以通过热疗进行选择性靶向。在 HPV 感染的细胞中，病毒 E7 mRNA 被 N6-甲基腺苷（m6A）修饰，并通过 IGF2BP1 稳定，IGF2BP1 是一种细胞 m6A 阅读器。热疗通过破坏 IGF2BP1 而非经典热休克蛋白来下调 E7 mRNA 和蛋白，从而在体外和体内逆转 HPV 相关的癌变。在机制上，热疗仅在存在 m6A 修饰的 E7 mRNA 的情况下促进 IGF2BP1 聚集，以形成独特的热诱导 m6A E7 mRNA-IGF2BP1 颗粒，这些颗粒被泛素-蛋白酶体系统解决。总的来说，我们的研究结果不仅显示了 m6A RNA 与其阅读器之间的相互调节，还为 HPV 相关恶性肿瘤提供了一种基于热疗的治疗策略，通过特异性地下调 E7 mRNA-IGF2BP1 致癌复合物。