Li Jin-Xin, Zhang Jing, Li Cheng-Hao, Zhang Qing, Kong Beihua, Wang Pei-Hui
Department of Infectious Disease and Hepatology, The Second Hospital of Shandong University, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China.
Front Immunol. 2025 Apr 8;16:1555629. doi: 10.3389/fimmu.2025.1555629. eCollection 2025.
Human papillomavirus (HPV) is a major cause of cancers and benign lesions. High-risk (HR) types, including HPV16 and HPV18, are strongly implicated in cervical and other malignancies, while low-risk (LR) types, such as HPV11, are predominantly associated with benign conditions. Although the immune evasion of HPV oncoproteins E6 and E7 are extensively studied, the immunomodulatory functions of the E2 protein remain poorly underexplored. This study elucidates the role of HPV11 and HPV16 E2 proteins in modulating innate immune responses, focusing on their interaction with key innate antiviral signaling pathways. We demonstrate that HPV11 and HPV16 E2 proteins effectively suppress the activation of pivotal antiviral signaling pathways, including RIG-I/MDA5-MAVS, TLR3-TRIF, cGAS-STING, and JAK-STAT. Mechanistic analyses reveal that E2 proteins interact with the core components of type I interferon (IFN)-inducing pathways, inhibiting IRF3 phosphorylation and nuclear translocation, thereby attenuating IFN expression. Additionally, E2 disrupts the JAK-STAT signaling cascade by preventing the assembly of the ISGF3 complex, comprising STAT1, STAT2, and IRF9, ultimately inhibiting the transcription of interferon-stimulated genes (ISGs). These findings underscore the broader immunosuppressive role of HPV E2 proteins, complementing the well-established immune evasion mechanisms mediated by E6 and E7. This work advances our understanding of HPV-mediated immune evasion and positions the E2 protein as a promising target for therapeutic strategies aimed at augmenting antiviral immunity in HPV-associated diseases.
人乳头瘤病毒（HPV）是癌症和良性病变的主要病因。包括HPV16和HPV18在内的高危（HR）型与宫颈癌及其他恶性肿瘤密切相关，而低危（LR）型，如HPV11，主要与良性病变相关。尽管对HPV癌蛋白E6和E7的免疫逃逸进行了广泛研究，但E2蛋白的免疫调节功能仍未得到充分探索。本研究阐明了HPV11和HPV16 E2蛋白在调节先天免疫反应中的作用，重点关注它们与关键先天抗病毒信号通路的相互作用。我们证明，HPV11和HPV16 E2蛋白能有效抑制关键抗病毒信号通路的激活，包括RIG-I/MDA5-MAVS、TLR3-TRIF、cGAS-STING和JAK-STAT。机制分析表明，E2蛋白与I型干扰素（IFN）诱导通路的核心成分相互作用，抑制IRF3磷酸化和核转位，从而减弱IFN表达。此外，E2通过阻止由STAT1、STAT2和IRF9组成的ISGF3复合物的组装，破坏JAK-STAT信号级联反应，最终抑制干扰素刺激基因（ISG）的转录。这些发现强调了HPV E2蛋白更广泛的免疫抑制作用，补充了由E6和E7介导的成熟免疫逃逸机制。这项工作增进了我们对HPV介导的免疫逃逸的理解，并将E2蛋白定位为旨在增强HPV相关疾病抗病毒免疫力的治疗策略的有希望的靶点。
