Rip Proteins in Innate Immune Signaling

含丝氨酸/苏氨酸激酶Ripk 1的死亡结构域是TNF诱导的细胞凋亡的核心成分。 信号传导复合物介导NF B和MAP激酶活化、凋亡和另一种形式的 非胱天蛋白酶依赖性细胞死亡，称为坏死性凋亡。在无偏见的基因组范围的siRNA筛选监管机构 Ripk 1，其去泛素化酶Cyld，相关的Ripk 3以及其他属于坏死性凋亡的蛋白质， 干扰素和Toll样受体信号系统。这些研究和那些使用 变构Ripk 1激酶抑制剂或Ripk 3缺陷小鼠建立坏死性凋亡作为主要的宿主防御 抵抗病毒感染坏死性凋亡需要Ripk 1和Ripk 3的激酶活性， 激酶启动和执行坏死性细胞死亡是未知的。我们已经证明，Ripk 1具有额外的 在TLR 3和Rig-I介导的核酸传感途径中，我们 初步研究还表明，Ripk 1参与了涉及Sting、Tbk 1 Irf3总的来说，这些研究预测了Ripk 1在先天性抗病毒免疫中的核心作用，然而， 与Ripk 1缺陷相关的围产期致死性已经排除了体内分析。当前的目标 我们的建议是使用条件性免疫应答测试抗病毒先天免疫应答中对Ripk 1的需求。 Ripk 1小鼠。我们还在Ripk 1基因座中引入了一个突变， Ripk 1激酶活性。我们对Ripk 1激酶失活的MEFs和巨噬细胞的初步研究发现， 分别保护细胞免受TNF和TLR 3诱导的坏死性凋亡。这一目标的另一个目的是 我们的建议是研究病毒引发的坏死性凋亡对这些新病毒中宿主防御的贡献。 工程化Ripk 1激酶失活小鼠。除了病毒诱导的损伤和炎症，Rip激酶 响应于非微生物信号，称为非微生物相关分子模式（DAMP）， 组织损伤这些研究的长期目标是选择性抑制无菌性炎症中的Rip激酶 而不损害先天免疫力。

The death domain containing serine/threonine kinase Ripk1 is the core component of TNF-induced signaling complexes mediating NF¿B and MAP kinase activation, apoptosis and an alternative form of caspase independent cell death called necroptosis. In unbiased genome wide siRNA screens for regulators of necroptosis, Ripk1, its deubiquitinase Cyld, the related Ripk3 as well as other proteins belonging to the interferon and Toll-like receptor signaling systems were identified. These studies and those using an allosteric Ripk1 kinase inhibitor or Ripk3-deficient mice establish necroptosis as a prominent host defense against viral infection. Necroptosis requires the kinase activities of Ripk1 and Ripk3 but precisely how Rip kinases initiate and execute necroptotic cell death is unknown. We have shown that Ripk1 has additional signaling functions beyond TNF, in nucleic acid sensing pathways mediated by TLR3 and Rig-I. Our preliminary studies additionally implicate Ripk1 in a cytosolic DNA sensing pathway involving Sting, Tbk1 and Irf3. Collectively, these studies predict a central role for Ripk1 in innate anti-viral immunity, however the perinatal lethality associated with a Ripk1-deficiency has precluded in vivo analyses. Goals of the current proposal are to test a requirement for Ripk1 in the anti-viral innate immune response using the conditional Ripk1 mice we have generated. We have also introduced a mutation into the Ripk1 locus that impairs the kinase activity of Ripk1. Our preliminary studies in Ripk1 kinase inactive MEFs and macrophages find these cells protected from TNF- and TLR3-induced necroptosis, respectively. An additional objective of this proposal is to examine the contribution of viral-initiated necroptosis to host defense in these newly engineered Ripk1 kinase inactive mice. In addition to virus-induced injury and inflammation, Rip kinases respond to non-microbial signals called danger-associated molecular patterns (DAMPs) released upon tissue injury. The long-term goal of these studies is to selectively inhibit Rip kinases in sterile inflammation without impairing innate immunity.