LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death.
LIMD1 is induced by and required for LMP1 signaling, and protects EBV-transformed cells from DNA damage-induced cell death.
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DOI：
10.18632/oncotarget.23676
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发表时间：
2018-01-19
期刊：
影响因子：
--
通讯作者：
Ning S
中科院分区：
文献类型：
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作者：
Wang L;Howell MEA;McPeak B;Riggs K;Kohne C;Yohanon JU;Foxler DE;Sharp TV;Moorman JP;Yao ZQ;Ning S
LIMD 1（含LIM结构域的蛋白1）被认为是一种肿瘤抑制因子，在许多癌症（包括血液恶性肿瘤）中被失调;然而，人们对其失调的潜在机制及其在致癌作用中的作用知之甚少。EB病毒（EBV）与一组淋巴细胞和上皮起源的恶性肿瘤有关。使用高通量表达谱分析，我们以前已经确定LIMD 1作为一个共同的标志物与致癌转录因子IRF 4在EBV相关的淋巴瘤和其他血液恶性肿瘤。在这项研究中，我们已经确定了潜在的保守的IRF 4和NFκ B结合基序在LIMD 1基因启动子，并证明这两个功能的启动子-报告分析。我们进一步表明，LIMD 1部分上调EB病毒潜伏膜蛋白1（LMP 1）通过IRF 4和NFκB在EB病毒潜伏期。至于它在EB病毒潜伏感染中的作用，我们发现LIMD 1与TRAF 6相互作用，TRAF 6是LMP 1信号转导的关键介质。重要的是，LIMD 1缺失损害LMP 1信号传导和功能，增强离子霉素诱导的DNA损伤和凋亡，并抑制p62介导的选择性自噬。总之，这些结果表明，LIMD 1在EBV潜伏期上调，并发挥致癌作用，而不是肿瘤抑制因子。我们的研究结果已经确定LIMD 1作为EBV潜伏期和肿瘤发生的新参与者，并开辟了一条新的研究途径，其中LIMD 1和p62在连接DNA损伤反应（DDR），凋亡和自噬及其在病毒肿瘤发生过程中的潜在相互作用中发挥关键作用。
LIMD1 (LIM domain-containing protein 1) is considered as a tumor suppressor, being deregulated in many cancers to include hematological malignancies; however, very little is known about the underlying mechanisms of its deregulation and its roles in carcinogenesis. Epstein-Barr Virus (EBV) is associated with a panel of malignancies of lymphocytic and epithelial origin. Using high throughput expression profiling, we have previously identified LIMD1 as a common marker associated with the oncogenic transcription factor IRF4 in EBV-related lymphomas and other hematological malignancies. In this study, we have identified potential conserved IRF4- and NFκB-binding motifs in the LIMD1 gene promoter, and both are demonstrated functional by promoter-reporter assays. We further show that LIMD1 is partially upregulated by EBV latent membrane protein 1 (LMP1) via IRF4 and NFκB in EBV latency. As to its role in the setting of EBV latent infection, we show that LIMD1 interacts with TRAF6, a crucial mediator of LMP1 signal transduction. Importantly, LIMD1 depletion impairs LMP1 signaling and functions, potentiates ionomycin-induced DNA damage and apoptosis, and inhibits p62-mediated selective autophagy. Taken together, these results show that LIMD1 is upregulated in EBV latency and plays an oncogenic role rather than that of a tumor suppressor. Our findings have identified LIMD1 as a novel player in EBV latency and oncogenesis, and open a novel research avenue, in which LIMD1 and p62 play crucial roles in linking DNA damage response (DDR), apoptosis, and autophagy and their potential interplay during viral oncogenesis.