Abstract：
Receptor interacting protein kinase 3 (RIPK3) is an intracellular kinase at the crossroads of cell death and inflammation. RIPK3 contains a RIP homotypic interaction motif (RHIM) domain which allows interactions with other RHIM-containing proteins and a kinase domain that allows phosphorylation of target proteins. RIPK3 may be activated through interaction with RHIM-containing proteins such as RIPK1, TRIF and DAI (ZBP1, DLM-1) or through RHIM-independent mechanisms in an alkaline intracellular pH. RIPK3 mediates necroptosis and promotes inflammation, independently of necroptosis, through either activation of NFκB or the inflammasome. There is in vivo preclinical evidence of the contribution of RIPK3 to both acute kidney injury (AKI) and chronic kidney disease (CKD) and to the AKI-to-CKD transition derived from RIPK3 deficient mice or the use of small molecule RIPK3 inhibitors. In these studies, RIPK3 targeting decreased inflammation but kidney injury improved only in some contexts. Clinical translation of these findings has been delayed by the potential of some small molecule inhibitors of RIPK3 kinase activity to trigger apoptotic cell death by inducing conformational changes of the protein. A better understanding of the conformational changes in RIPK3 that trigger apoptosis, dual RIPK3/RIPK1 inhibitors or repurposing of multiple kinase inhibitors such as dabrafenib may facilitate clinical development of the RIPK3 inhibition concept for diverse inflammatory diseases, including kidney diseases.
摘要：
受体相互作用蛋白激酶3（RIPK3）是处于细胞死亡和炎症十字路口的细胞内激酶。RIPK3含有允许与其他含RHIM的蛋白质相互作用的RIP同型相互作用基序(RHIM)结构域和允许靶蛋白磷酸化的激酶结构域。RIPK3可以通过与含RHIM的蛋白质如RIPK1、TRIF和DAI(ZBP1、DLM-1)相互作用或通过在碱性细胞内pH中不依赖RHIM的机制而被激活。RIPK3介导坏死和促进炎症，独立于坏死，通过激活NFκB或炎症小体。有体内临床前证据表明，RIPK3对急性肾损伤（AKI）和慢性肾病（CKD）以及源自RIPK3缺陷小鼠或使用小分子RIPK3抑制剂的AKI到CKD转变的贡献。在这些研究中,RIPK3靶向减少炎症，但肾损伤仅在某些情况下改善。RIPK3激酶活性的一些小分子抑制剂通过诱导蛋白质的构象变化来触发凋亡细胞死亡的潜力已延迟了这些发现的临床翻译。更好地理解RIPK3引发细胞凋亡的构象变化，双重RIPK3/RIPK1抑制剂或多种激酶抑制剂如dabrafenib的再利用可能促进RIPK3抑制概念在各种炎症性疾病的临床发展，包括肾脏疾病。
