Regulation of Necroptosis and inflammation

摘要 术语程序性坏死或坏死性下垂用于区分几种类型的细胞死亡 如细胞凋亡、自噬和上睑下垂。坏死性上睑下垂与炎症反应和 疾病，这是肿瘤发生和发展的一个促成因素。蛋白激酶RIP1和RIP3 对坏死性下垂的激活至关重要。许多研究表明，两种生物之间存在复杂的功能相互作用。 RIP1和RIP3在调节坏死体形成和坏死性下垂中的作用。这条通路的错误调节会引发 组织内环境不稳定、炎症反应和癌变的发生或发展。例如, RIP3诱导的肠上皮异常坏死性下垂导致炎症性肠病，这与 与结直肠癌的发展密切相关。虽然RIP3在坏死性下垂中是一个关键的激酶，但RIP3是如何 在细胞中的调控尚不清楚。我们最近发现，Parkin在坏死性下垂过程中调节RIP3。帕金是一个 E3泛素连接酶，由PARK2基因编码。PARK2基因突变是最常见的 常染色体隐性遗传性早发帕金森病的原因新出现的证据表明 帕金还发挥着肿瘤抑制因子的作用，尽管帕金如何发挥肿瘤抑制因子的作用仍然存在。 不清楚。最近，我们发现Parkin是坏死性下垂和炎症的负调节因子。停车 促进RIP3泛素化，抑制RIP3磷酸化、坏死体形成和坏死性下垂 细胞。相反，Parkin基因的缺失会导致坏死性下垂的增加。重要的是，删除 PARK2基因在体内促进炎症和增殖。有趣的是，我们还发现帕金本身 受AMP激活的蛋白激酶(AMPK)调节。根据这些初步结果，我们假设 AMPK-Parkin通路是促进RIP3泛素化的重要负性调节因子 和失活。此外，AMPK-Parkin-RIP3通路抑制炎症诱导 肿瘤发生学。为了验证这一假说，我们提出了以下具体目标：1.研究帕金的作用 在RIP3调节和坏死性下垂中的作用；2.研究AMPK对Parkin的调节；3.研究AMPK在RIP3调控中的作用 帕金患有炎症和癌症。这些研究将揭示Parkin在RIP3调控中的新角色， 坏死性下垂和炎症。此外，帕金作为肿瘤发挥作用的新机制 抑制者将会揭晓。因此，这些研究将对癌症的发病机制和 未来的癌症预防。 好了！

Abstract The term programmed necrosis or necroptosis has been used to distinguish several types of cell death such as apoptosis, autophagy, and pyroptosis. Necroptosis has been linked to inflammation response and diseases, which is a contributing factor for tumor initiation and progression. The protein kinase RIP1 and RIP3 are critical for the activation of necroptosis. Many studies have shown a complex functional interplay between RIP1 and RIP3 in regulating necrosome formation and necroptosis. Misregulation of this pathway would trigger abnormal tissue homeostasis, inflammation response, and caner initiation or progression. For example, abnormal RIP3-induced necroptosis in intestinal epithelium cause inflammatory bowel disease, which is linked to the development of colorectal cancer. Although RIP3 is a crucial kinase in necroptosis, how RIP3 is regulated in cells is not clear. We recently found that Parkin regulates RIP3 during necroptosis. Parkin is an E3 ubiquitin ligase that is encoded by the PARK2 gene. Mutation in the PARK2 gene is the most frequent cause of autosomal recessive early onset of Parkinson's Disease (PD). Emerging evidence suggests that Parkin also functions as a tumor suppressor, although how Parkin functions as a tumor suppressor remains unclear. Recently, we found that Parkin is a negative regulator of necroptosis and inflammation. Parkin promotes RIP3 ubiquitination, inhibits RIP3 phosphorylation, necrosome formation, and necroptosis in various cells. Conversely, deletion of the Parkin gene results in increased necroptosis. Importantly, deletion of the Park2 gene promotes inflammation and hyperplasia in vivo. Interestingly, we also found that Parkin itself is regulated by AMP-activated protein kinase (AMPK). Based on these preliminary results, we hypothesize that the AMPK-Parkin pathway is an important negative regulator of RIP3 by promoting RIP3 ubiquitination and inactivation. Further, the AMPK-Parkin-RIP3 pathway suppresses inflammation-induced tumorigenesis. To test this hypothesis, we propose the following Specific Aims: 1. To study the role of Parkin in RIP3 regulation and necroptosis; 2. To study the regulation of Parkin by AMPK; 3. To study the role of Parkin in inflammation and cancer. These studies will reveal a novel role of Parkin in the regulation of RIP3, necroptosis, and inflammation. In addition, a new mechanism by which Parkin functions as a tumor suppressor will be revealed. Accordingly, these studies will have a high impact for cancer pathogenesis and future cancer prevention. !