Prion protein is required for tumor necrosis factor α (TNFα)-triggered nuclear factor κB (NF-κB) signaling and cytokine production.
Prion protein is required for tumor necrosis factor α (TNFα)-triggered nuclear factor κB (NF-κB) signaling and cytokine production.
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朊病毒蛋白是肿瘤坏死因子 (TNF) 触发的核因子 B (NF-B) 信号传导和细胞因子产生所必需的
DOI：
10.1074/jbc.m117.787283
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发表时间：
2017-11-17
期刊：
影响因子：
--
通讯作者：
Li CY
中科院分区：
文献类型：
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作者：
Wu GR;Mu TC;Gao ZX;Wang J;Sy MS;Li CY
正常细胞朊病毒蛋白（PrP）的表达是朊病毒疾病发病机制所必需的。然而，PrP 的生理功能仍然不明确。在这里，我们确定 PrP 对于人类黑色素瘤细胞系 M2 和胰腺导管细胞腺癌细胞系 BxPC-3 中的肿瘤坏死因子 (TNF) α 触发信号传导至关重要。在 M2 细胞中，TNFα 上调 p-IκB 激酶 α/β (p-IKKα/β)、p-p65 和 p-JNK 的表达，但下调 IκBα 蛋白，所有这些蛋白都是 TNF 受体信号级联中的下游信号中间体。当 M2 细胞中 PRNP 被删除时，TNFα 的作用就不再可检测到。更重要的是，当 PRNP 重新引入 PRNP 无效细胞时，p-p65 和 p-JNK 反应会恢复。 TNFα 还能激活 NF-κB 并增加野生型 M2 细胞中 TNFα 的产生，但在 PrP 无效的 M2 细胞中则不然。在 BxPC-3 细胞中也获得了类似的结果。此外，TNFα 激活 NF-κB 需要受体相互作用丝氨酸/苏氨酸激酶 1 (RIP1) 和 TNF 受体相关因子 2 (TRAF2) 泛素化。 TNFα 处理增加 PrP 与去泛素酶肿瘤抑制因子圆柱瘤 (CYLD) 之间的结合，在这些处理的细胞中，CYLD 与 RIP1 和 TRAF2 的结合减少。我们得出结论，PrP 捕获 CYLD，阻止其结合 RIP1 和 TRAF2 并使其去泛素化。我们的研究结果表明，PrP 增强对 TNFα 的反应，促进促炎细胞因子的产生，这可能有助于炎症和肿瘤发生。
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 up-regulates the expression of p-IκB-kinase α/β (p-IKKα/β), p-p65, and p-JNK, but down-regulates 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 wild-type 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.