Xu Yang, Zhang Ji, Ma Lingsong, Zhao Shoucai, Li Shizun, Huang Tingting, Chu Zhaohu
Department of Neurology, First Affiliated Hospital of Wannan Medical College, No. 2, ZheShanXi Road, Wuhu 241001, China.
Non-Coding RNA of Major Diseases Research Center, Central Laboratory, First Affiliated Hospital of Wannan Medical College, No. 2, ZheShanXi Road, Wuhu 241001, China.
Behav Neurol. 2018 Jul 22;2018:6814393. doi: 10.1155/2018/6814393. eCollection 2018.
Necroptosis is the best-described form of regulated necrosis at present, which is widely recognized as a component of caspase-independent cell death mediated by the concerted action of receptor-interacting protein kinase 1 (RIPK1) and receptor-interacting protein kinase 3 (RIPK3). Mixed-lineage kinase domain-like (MLKL) was phosphorylated by RIPK3 at the threonine 357 and serine 358 residues and then formed tetramers and translocated onto the plasma membrane, which destabilizes plasma membrane integrity leading to cell swelling and membrane rupture. Necroptosis is downstream of the tumor necrosis factor (TNF) receptor family, and also interaction with NOD-like receptor pyrin 3 (NLRP3) induced inflammasome activation. Multiple inhibitors of RIPK1 and MLKL have been developed to block the cascade of signal pathways for procedural necrosis and represent potential leads for drug development. In this review, we highlight recent progress in the study of roles for necroptosis in cerebral ischemic disease and discuss how these modifications delicately control necroptosis.
坏死性凋亡是目前描述最为详尽的一种程序性坏死形式，它被广泛认为是由受体相互作用蛋白激酶1（RIPK1）和受体相互作用蛋白激酶3（RIPK3）协同作用介导的半胱天冬酶非依赖性细胞死亡的一个组成部分。混合谱系激酶结构域样蛋白（MLKL）在苏氨酸357和丝氨酸358残基处被RIPK3磷酸化，然后形成四聚体并转位到质膜上，这会破坏质膜完整性，导致细胞肿胀和膜破裂。坏死性凋亡位于肿瘤坏死因子（TNF）受体家族的下游，并且还与NOD样受体吡喃素3（NLRP3）相互作用诱导炎性小体激活。已经开发出多种RIPK1和MLKL抑制剂来阻断程序性坏死的信号通路级联反应，并代表了药物开发的潜在先导物。在本综述中，我们重点介绍了坏死性凋亡在脑缺血疾病中作用研究的最新进展，并讨论了这些修饰如何精细地控制坏死性凋亡。
