Ahn Dae-Gyun, Sharif Tanveer, Chisholm Kenneth, Pinto Devanand M, Gujar Shashi A, Lee Patrick W K
a Department of Microbiology and Immunology ; Dalhousie University ; Halifax , Nova Scotia , Canada.
Cell Cycle. 2015;14(14):2301-10. doi: 10.1080/15384101.2015.1044187. Epub 2015 May 6.
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.
Ras信号失调是多种癌症的主要原因。然而，异常的Ras信号为许多病毒提供了有利环境，使它们成为有潜力的抗癌治疗药物。癌细胞对这类病毒的易感性主要是由于I型干扰素（IFN）反应受损，这通常是这些细胞中Ras/ERK信号激活的结果。在本研究中，我们寻找受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细胞发生Ras转化后，Nogo-B（网蛋白4）的N端被蛋白酶切割。有趣的是，在未转化和Ras转化的细胞中敲低Nogo（KD）均增强了病毒诱导的IFN反应，这表明切割和未切割的Nogo均能抑制IFN反应。然而，在Ras转化细胞中对Nogo切割进行药理学阻断可显著增强病毒诱导的IFN反应，这表明切割后的Nogo有助于增强这些细胞中的IFN抑制作用。我们进一步表明，与Ras诱导的Nogo-B切割相关的IFN抑制不同于但与与激活的Ras/ERK途径相关的IFN抑制协同。因此，我们的研究揭示了Nogo-B及其切割在致癌性Ras转化抑制抗病毒免疫反应中的重要新作用。
