中科院武汉病毒所在朊病毒致肿瘤恶性转化的研究中取得新进展

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朊病毒是正常蛋白错误折叠后形成的一种异常蛋白质。作为一种病原体，朊病毒因其能够引发包括疯牛病在内的退行性脑病而广为人知。近期，中国科学院武汉病毒研究所李朝阳研究员课题组揭示肿瘤细胞表达的原朊病毒蛋白应答肿瘤坏死因子的分子机制，相关成果“Prion protein is required for tumor necrosis factor alpha (TNFα)-triggered nuclear factor kappa B (NF-κB)  signaling and cytokine production”近日发表在Journal of Biological Chemistry上。

近年来，多项研究表明朊病毒蛋白PrP在多种肿瘤中出现高表达并与胰腺癌、胃癌和乳腺癌患者的预后呈现关联。阐明朊病毒蛋白如何促进肿瘤恶性转化是理解该蛋白作为预后差的生物学标记的分子基础。通过对恶性黑色素瘤细胞株M2和胰腺癌细胞株BxPC3的研究，该课题组发现细胞膜表面的朊病毒蛋白可以结合去泛素化酶CYLD。在肿瘤坏死因子（一种能够直接杀伤肿瘤细胞而对正常细胞无明显毒性的细胞因子）处理的条件下，CYLD和朊病毒蛋白的结合能力增强，从而减少CYLD和肿瘤坏死因子复合体中RIP1和TRAF2的结合能力，导致RIP1和TRAF2的泛素化水平上升并进而下调NFκ
信号通路。由于部分癌前病变组织中会出现朊病毒蛋白的表达，本研究揭示了原朊病毒蛋白可能应答长期慢性炎症反应，在炎癌转变中起一定的作用。



该研究得到国家自然科学基金委员会（31670170）、中科院先导A类项目（XDA12010309）和病毒学国家重点实验室资助。项目由博士研究生吴桂茹为主完成。

Prion protein is required for tumor necrosis factor alpha (TNFα)-triggered nuclear factor kappa B (NF-κB) signaling and cytokine production

Abstract
The expression of normal cellular prion protein (PrP) is required for the pathogenesis of prion diseases. However, the physiological functions of PrP remain ambiguous. Here, we identified PrP as being critical for tumor necrosis factor (TNF)α-triggered signaling in a human melanoma cell line, M2, and a pancreatic ductal cell adenocarcinoma cell line, BxPC-3. In M2 cells, TNFα upregulates the expression ofp-I-kappa-B-kinase α/β (p-IKKα/β), p-p65, and p-JNK, but downregulates the IκBα protein, all of which are downstream signaling intermediates in the TNF receptor signaling cascade. When PRNP is deleted in M2 cells, the effects of TNFα are no longer detectable. More importantly, p-p65 and p-JNK responses are restored when PRNP is reintroduced into the PRNP null cells. TNFα also activates NF-κB and increases TNFα production in wildtype M2 cells, but not in PrP-null M2 cells. Similar results are obtained in the BxPC-3 cells. Moreover, TNFα activation of NF-κB requires ubiquitination of receptor-interacting serine/threonine kinase 1 (RIP1) and TNF receptor-associated factor 2 (TRAF2). TNFα treatment increases the binding between PrP and the deubiquitinase tumor suppressor cylindromatosis (CYLD), in these treated cells, binding of CYLD to RIP1 and TRAF2 is reduced. We conclude that PrP traps CYLD, preventing it from binding and deubiquitinating RIP1 and TRAF2. Our findings reveal that PrP enhances the responses to TNFα, promoting proinflammatory cytokine production, which may contribute to inflammation and tumorigenesis.

原文链接：
http://www.jbc.org/content/early/2017/09/13/jbc.M117.787283.abstract
本文来源：武汉病毒所官网