HPV E6通过调节角质细胞分化承诺和YAP1激活来抑制E6AP调节上皮质平衡
Wen Yin1, Nagayasu Egawa1, Ke Zheng1
1Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
PLoS pathogens
|June 28, 2023
概括
人类乳头瘤病毒 (HPV) 通过向E6AP和NHERF1.1来破坏上皮质平衡. 这些病毒瘤蛋白改变细胞密度,细胞循环和分化,影响受感染的组织并涉及YAP信号传递.
科学领域:
- 细胞生物学 细胞生物学
- 病毒学 病毒学
- 分子生物学分子生物学
背景情况:
- 人类乳头瘤病毒 (HPV) 通过破坏上皮质平衡来建立持久性感染.
- HPV 的 E6 上蛋白是细胞失调的关键驱动因素.
- 表皮稳态包括复杂的过程,如细胞密度,细胞循环控制和分化.
研究的目的:
- 阐明E6AP和NHERF1的调节作用,这是HPVE6蛋白的细胞点,在维持上皮质平衡中发挥作用.
- 研究HPV11和HPV16E6型蛋白如何调节状细胞表型和信号通路.
- 确定E6AP和NHERF1与E6相互作用在HPV诱导的细胞变化中的特定贡献.
主要方法:
- 利用FUCCI和细胞对细胞竞争试验来研究角质细胞的行为.
- 对于E6AP和NHERF1.1,使用的枯竭和突变表达策略.
- 进行RNA测序以分析转录特征和YAP目标基因激活.
- 分析了感染HPV的患者组织 (淋巴瘤) 和器官类型的培养物.
主要成果:
- 缺少E6AP或HPV11/16E6的表达增加了角质细胞密度,细胞周期活性和延迟分化.
- 感染HPV11和16的组织显示细胞密度增加和分化延迟,反映了实验结果.
- 与未感染的上皮相比,E6AP和NHERF1在HPV11淋巴瘤组织中减少.
- 失去HPV11的E6/E6AP结合取消了稳态调节;失去E6/NHERF1结合改变了分化值.
- RNA测序揭示了YAP目标基因诱导和分化基因在E6-表达和E6AP-/-细胞中的下调.
- 在各种系统中,HPV11 E6激活了Yap,其中E6AP和NHERF1发挥了关键作用.
结论:
- 阿尔法组HPV E6蛋白通过与E6AP保持的相互作用来调节状细胞的表型和上皮的恒常性.
- 这些相互作用导致下游路径的改变,包括涉及NHERF1和YAP的路径.
- E6AP对于HPV16的E6恒温功能至关重要,而NHERF1的作用则根据特定的E6蛋白更为细致.
- 这项研究为HPV E6蛋白质如何劫持细胞机械以促进持久感染提供了一个模型.
相关概念视频
Abnormal Proliferation
4.6K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.6K
Negative Regulator Molecules
35.5K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.5K
Mitogens and the Cell Cycle
6.6K
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
6.6K
Inhibition of Cdk Activity
4.8K
The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...
4.8K
Renewal of Skin Epidermal Stem Cells
2.6K
The skin is divided into epidermis, dermis, and hypodermis, the skin's outermost, middle, and inner layers. The human epidermal layer regularly undergoes renewal, where old, dead cells are replaced by new cells. Epidermal stem cells or EpiSCs divide and differentiate to restore the lost cells. For the renewal process, some EpiSCs continuously self-renew. In contrast, few others differentiate into transit-amplifying cells, which later form prickle or spinous cells, followed by granular...
2.6K
Role of Ephrin-Eph Signalling in Intestinal Stem Cell Renewal
2.3K
Erythropoietin-producing hepatocellular carcinoma receptor (Eph) and its ligand, Eph receptor-interacting protein (Ephrin) were first discovered in the human carcinoma cell line, hence the name. Ephrin-Eph interaction guides cells to reach their appropriate location in adult tissues. They also play an essential role in the immune system by helping in immune cell migration, adhesion, and activation. Based on their structure and function, Eph is divided into two classes — EphA and EphB.
2.3K


