The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation
The human papillomavirus E6 protein targets apoptosis-inducing factor (AIF) for degradation
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DOI：
10.1038/s41598-020-71134-3
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发表时间：
2020-08-26
影响因子：
4.6
通讯作者：
Okuda, Kenji
中科院分区：
文献类型：
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作者：
Shimada, Masaru;Yamashita, Akio;Okuda, Kenji
高危人乳头瘤病毒（HPV）的癌蛋白E6在诱导细胞永生化和恶性肿瘤中起关键作用。E6通过降解p53下调caspase依赖通路。然而，HPV E6对其他途径的影响仍在研究中。在本研究中，我们发现HPV E6直接结合凋亡诱导因子（AIF）的所有三种形式（前体，成熟和凋亡），并与凋亡AIF共定位。在HPV16（一种致癌型HPV）衍生的E6存在时，这种结合诱导了mg132对AIF表达的敏感降低。相反，从非致癌型HPV衍生的E6， HPV6 (6E6)，尽管与AIF相互作用，但并没有降低AIF的水平。流式细胞分析显示，16E6抑制aif诱导的染色质降解（caspase非依赖性细胞凋亡的指标）和staurosporine（一种蛋白激酶抑制剂）诱导的细胞凋亡，而不是6E6。AIF敲除可减少sts诱导的16e6和6e6表达细胞的凋亡；然而，表达16e6的细胞的下降幅度低于表达6e6的细胞。这些发现表明，16E6而不是6E6能够阻断AIF介导的细胞凋亡，并且AIF可能是hpv诱导的宫颈癌的一个新的治疗靶点。
Oncoprotein E6 of high-risk human papillomavirus (HPV) plays a critical role in inducing cell immortalization and malignancy. E6 downregulates caspase-dependent pathway through the degradation of p53. However, the effect of HPV E6 on other pathways is still under investigation. In the present study, we found that HPV E6 directly binds to all three forms (precursor, mature, and apoptotic) of apoptosis-inducing factor (AIF) and co-localizes with apoptotic AIF. This binding induced MG132-sensitive reduction of AIF expression in the presence of E6 derived from HPV16 (16E6), a cancer-causing type of HPV. Conversely, E6 derived from a non-cancer-causing type of HPV, HPV6 (6E6), did not reduce the levels of AIF despite its interaction with AIF. Flow cytometric analysis revealed that 16E6, but not 6E6, suppressed apoptotic AIF-induced chromatin degradation (an indicator of caspase-independent apoptosis) and staurosporine (STS, a protein kinase inhibitor)induced apoptosis. AIF knockdown reduced STS-induced apoptosis in both of 16E6-expressing and 6E6-expressing cells; however, the reduction in 16E6-expressing cells was lower than that in 6E6-expressing cells. These findings indicate that 16E6, but not 6E6, blocks AIF-mediated apoptosis, and that AIF may represent a novel therapeutic target for HPV-induced cervical cancer.