Department of Microbiology and Immunology, Sidney Kimmel Cancer Center Thomas Jefferson University, 233S. 10th St, Philadelphia, PA, 19107, USA.
Cell Death Dis. 2019 Mar 13;10(3):245. doi: 10.1038/s41419-019-1490-8.
RIPK1 has emerged as a key effector in programmed necrosis or necroptosis. This function of RIPK1 is mediated by its protein serine/threonine kinase activity and through the downstream kinase RIPK3. Deletion of RIPK1 prevents embryonic lethality in mice lacking FADD, a signaling adaptor protein required for activation of Caspase 8 in extrinsic apoptotic pathways. This indicates that FADD-mediated apoptosis inhibits RIPK1-dependent necroptosis to ensure successful embryogenesis. However, the molecular mechanism for this critical regulation remains unclear. In the current study, a novel mouse model has been generated, by disrupting a potential caspase cleavage site at aspartic residue (D)324 in RIPK1. Interestingly, replacing D324 with alanine (A) in RIPK1 results in midgestation lethality, similar to the embryonic defect in FADD mice but in stark contrast to the normal embryogenesis of RIPK1 null mutant mice. Surprisingly, disrupting the downstream RIPK3 alone is insufficient to rescue RIPK1 mice from embryonic lethality, unless FADD is deleted simultaneously. Further analyses reveal a paradoxical role for RIPK1 in promoting caspase activation and apoptosis in embryos, a novel mechanism previously unappreciated.
RIPK1 已成为程序性细胞坏死或细胞坏死的关键效应因子。RIPK1 的这一功能是通过其蛋白丝氨酸/苏氨酸激酶活性和下游激酶 RIPK3 介导的。在缺乏 FADD 的情况下，RIPK1 的缺失可防止小鼠的胚胎致死，FADD 是外源性凋亡途径中激活 Caspase 8 所必需的信号接头蛋白。这表明 FADD 介导的细胞凋亡抑制 RIPK1 依赖性细胞坏死，以确保成功的胚胎发生。然而，这种关键调控的分子机制仍不清楚。在本研究中，通过破坏 RIPK1 中天门冬氨酸残基 (D)324 上的潜在半胱氨酸蛋白酶切割位点，产生了一种新型的小鼠模型。有趣的是，用丙氨酸 (A) 替换 RIPK1 中的 D324 会导致中期胚胎致死，类似于 FADD 小鼠的胚胎缺陷，但与 RIPK1 缺失突变小鼠的正常胚胎发生形成鲜明对比。令人惊讶的是，单独破坏下游的 RIPK3 不足以挽救 RIPK1 小鼠的胚胎致死，除非同时删除 FADD。进一步的分析揭示了 RIPK1 在促进胚胎中 Caspase 激活和凋亡中的矛盾作用，这是以前未被认识的一种新机制。
