SRSF3 degradation in liver disease and hepatocellular carcinoma

我们已经发表了在肝细胞中消除一种特定的RNA剪接因子SRSF 3会导致 慢性肝损伤，葡萄糖和脂质代谢中断，炎症，纤维化，最终肝 癌因此，剪接因子的缺失不会导致肿瘤，而是产生了癌症的易感性， 类似于肿瘤抑制基因。此后，我们发现SRSF 3的缺失见于早期肝病， 人类和小鼠都是如此，除了我们之前展示的在肝癌中丢失之外。而 在脂肪性肝病进展为脂肪性肝炎和肝硬化期间发生的病理变化 虽然已经有充分的文献记载，但我们仍然不知道为什么有些人可以保持相对良性的脂肪肝 而另一些进展到更多的肝病，包括肝硬化和癌症。 基于广泛的初步数据，我们发现SRSF 3蛋白具有短的半衰期，其 水平受到蛋白体降解的剧烈调节。这不是通常的泛素介导的途径， 而是一种新的途径，涉及响应脂质诱导的应激与NEDD 8蛋白缀合。我们 SRSF 3可能是决定肝病是否进展或稳定的看门人。一个 个体对疾病进展的易感性取决于SRSF 3对应激诱导的疾病的易感性。 降解因此，我们提出了一个全面的系列实验，以了解SRSF 3是如何 以及稳定SRSF 3和防止其降解是否可以阻止 进展为NASH、肝硬化和肝癌。这些研究将解决有关 蛋白质稳态和致癌作用的基本生物学过程，并将整合生物化学，细胞 以及在肝脏中缺乏特异性剪接因子的小鼠中进行生理学研究的分子生物学实验。 我们将确定靶向SRSF 3进行neddylation的E3-连接酶复合物的组分， 导致SRSF 3破坏的途径，以及SRSF 3缀合和解缀合的平衡如何 树立政治意识我们研究是否表达抗降解SRSF 3或阻断小鼠neddylation 将阻止早期肝病发展为炎症、纤维化和肝硬化，我们将确定 这种方法是否可以预防肝癌或用于逆转小鼠肝癌。

We have published that eliminating a particular RNA splicing factor SRSF3 in hepatocytes causes chronic liver damage, disruptions in glucose and lipid metabolism, inflammation, fibrosis, and eventually liver cancer. So the loss of the splicing factor does not cause tumors but rather creates a pre-disposition to cancer, similar to a tumor suppressor gene. We have since shown that loss of SRSF3 is found in early liver disease in both humans and mice, in addition to being lost in liver cancer which we had shown previously. While the pathological changes that occur during the progression of fatty liver disease to steatohepatitis and cirrhosis have been well documented, we still do not know why some people can maintain relatively benign fatty livers while others progress to more serve liver disease including liver cirrhosis and cancer. Based on extensive preliminary data, we have found that the SRSF3 protein has a short half-life and its levels are acutely regulated by proteosomal degradation. This is not the usual ubiquitin mediated pathway but rather a novel pathway involving conjugation to the NEDD8 protein in response to lipid-induced stress. We believe that SRSF3 may be the gatekeeper that determines whether liver disease progresses or is stable. An individual’s susceptibility to progression is determined by the susceptibility of SRSF3 to stress-induced degradation. So we are proposing a comprehensive series of experiments to understand how SRSF3 is degraded in response to stress and whether stabilizing SRSF3 and preventing its degradation can halt the progression to NASH, cirrhosis and liver cancer. These studies will address key questions concerning the fundamental biological process of protein homeostasis and carcinogenesis and will integrate biochemical, cell and molecular biological experiments with physiological studies in mice lacking specific splicing factors in liver. We will determine the components of the E3-ligase complex that targets SRSF3 for neddylation, the pathway leading to destruction of SRSF3, and how the balance of SRSF3 conjugation and deconjugation is maintained. We investigate whether expressing a degradation-resistant SRSF3 or blocking neddylation in mice will prevent the progression of early liver disease to inflammation, fibrosis and cirrhosis, and we will determine whether this approach prevents liver cancer or can be used to reverse liver cancer in mice.