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首页> 外文期刊>Cell cycle >Ras transformation results in cleavage of reticulon protein Nogo-B that is associated with impairment of IFN response
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Ras transformation results in cleavage of reticulon protein Nogo-B that is associated with impairment of IFN response

机译：Ras转化导致网织蛋白Nogo-B的切割，这与IFN反应的损伤有关

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摘要

Dysregulation of Ras signaling is the major cause of various cancers. Aberrant Ras signaling, however, provides a favorable environment for many viruses, making them suitable candidates as cancer-killing therapeutic agents. Susceptibility of cancer cells to such viruses is mainly due to impaired type I interferon (IFN) response, often as a result of activated Ras/ERK signaling in these cells. In this study, we searched for cellular factors modulated by Ras signaling and their potential involvement in promoting viral oncolysis. We found that upon Ras transformation of NIH-3T3 cells, the N-terminus of Nogo-B (reticulon 4) was proteolytically cleaved. Interestingly, Nogo knockdown (KD) in non-transformed and Ras-transformed cells both enhanced virus-induced IFN response, suggesting that both cleaved and uncleaved Nogo can suppress IFN response. However, pharmacological blockade of Nogo cleavage in Ras-transformed cells significantly enhanced virus-induced IFN response, suggesting that cleaved Nogo contributes to enhanced IFN suppression in these cells. We further showed that IFN suppression associated with Ras-induced Nogo-B cleavage was distinct from but synergistic with that associated with an activated Ras/ERK pathway. Our study therefore reveals an important and novel role of Nogo-B and its cleavage in the suppression of anti-viral immune responses by oncogenic Ras transformation.
机译：Ras信号转导异常是各种癌症的主要原因。但是，异常的Ras信号传导为许多病毒提供了良好的环境，使其成为杀灭癌症的治疗剂的合适候选者。癌细胞对此类病毒的敏感性主要是由于I型干扰素（IFN）反应受损，通常是这些细胞中激活的Ras / ERK信号转导的结果。在这项研究中，我们搜索了受Ras信号调节的细胞因子及其在促进病毒溶瘤中的潜在作用。我们发现，在NIH-3T3细胞经过Ras转化后，Nogo-B（网状蛋白4）的N端被蛋白水解切割。有趣的是，未转化的细胞和经过Ras转化的细胞中的Nogo敲低（KD）均可增强病毒诱导的IFN反应，这表明切割和未切割的Nogo均可抑制IFN反应。但是，在Ras转化的细胞中Nogo裂解的药理学阻断作用显着增强了病毒诱导的IFN反应，这表明裂解的Nogo有助于增强这些细胞中的IFN抑制。我们进一步表明，与Ras诱导的Nogo-B裂解相关的IFN抑制与激活的Ras / ERK途径相关的IFN抑制不同但具有协同作用。因此，我们的研究揭示了Nogo-B及其裂解在致癌性Ras转化抑制抗病毒免疫反应中的重要且新颖的作用。

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