Regulation of TNF Receptor-Mediated Apoptosis

描述(申请人提供)：肿瘤坏死因子与其受体TNFR1结合可触发细胞存活或细胞死亡，但决定这两种不同反应中哪一种被触发的机制仍未完全阐明。一个细胞死亡检查点是激活核因子-kappaB转录因子，随后诱导抗凋亡基因抑制细胞凋亡途径。初步研究表明，存在另一个受赖氨酸63连接的RIP1泛素化调节的细胞死亡检查点。RIP1上赖氨酸377的泛素化首先通过非依赖于NF-kappaB的机制抑制肿瘤坏死因子诱导的细胞凋亡，然后通过依赖于NF-kappaB的机制抑制肿瘤坏死因子诱导的细胞凋亡。相反，在没有泛素化的情况下，RIP1起着促凋亡信号分子的作用。因此，RIP1是一个双功能分子，可以是支持生存的，也可以是支持死亡的，这取决于它的泛素化状态，因此在肿瘤坏死因子信号转导的早期，RIP1作为一个非依赖于NF-kappaB的细胞死亡开关。这项研究建议研究这个细胞死亡检查点是如何被调控的。(1)RIP1泛素化或缺乏泛素化调控caspase激活的机制将被研究。(2)还将测试RIP1绑定合作伙伴对此检查点的贡献。(3)建立新的细胞死亡检查点基因修饰的动物模型，研究该检查点与免疫功能的相关性。从这些研究中获得的见解可能会导致开发能够调节这个细胞死亡检查点的药理学试剂。这类药物可能在肿瘤坏死因子发挥作用的炎症性疾病中具有治疗潜力。与公共卫生相关：肿瘤坏死因子是一种免疫系统激素，可导致类风湿性关节炎和克罗恩病。我们的目标是弄清楚肿瘤坏死因子是如何控制细胞寿命的，这样我们就有可能将其用于这些疾病的治疗目的。

DESCRIPTION (provided by applicant): TNF binding to its receptor TNFR1 triggers cell survival or cell death but the mechanisms that determine which of these two divergent responses is triggered remain to be fully elucidated. One cell death checkpoint is the activation of NF-kappaB transcription factors and subsequent induction of anti-apoptotic genes to inhibit the apoptosis pathway. Preliminary studies performed demonstrated the existence of another cell death checkpoint regulated by lysine 63-linked ubiquitination of RIP1. Ubiquitination of lysine 377 on RIP1 inhibits TNF-induced apoptosis first through an NF-kappaB-independent mechanism, and subsequently through an NF-kappaB- dependent mechanism. In contrast, in the absence of ubiquitination, RIP1 serves as a pro- apoptotic signaling molecule. Thus, RIP1 is a dual-function molecule that can be either pro-survival or pro-death depending on its ubiquitination state and thus serves as an NF- kappaB-independent cell death switch early in TNF signaling. This study proposes to examine how this cell death checkpoint may be regulated. (1) The mechanism by which ubiquitination of RIP1, or the lack of it, regulates the activation of caspases will be examined. (2) The contribution by RIP1-binding partners to this checkpoint will also be tested. (3) Animal models with genetic modifications in this novel cell death checkpoint will be developed to study the relevance of this checkpoint in immune function. Insights gained from these studies may lead to the development of pharmacological agents that can modulate this cell death checkpoint. Such agents may have therapeutic potential in inflammatory diseases where TNF plays a role. PUBLIC HEALTH RELEVANCE: TNF is an immune system hormone that contributes to rheumatoid arthritis and Crohn's Disease. Our aim is to figure out how TNF controls the lifespan of cells so that we can potentially manipulate this for therapeutic purposes in these diseases.