Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis
Ubiquitination of RIPK1 suppresses programmed cell death by regulating RIPK1 kinase activation during embryogenesis
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RIPK1 泛素化通过在胚胎发生过程中调节 RIPK1 激酶激活来抑制程序性细胞死亡
DOI：
10.1038/s41467-019-11839-w
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发表时间：
2019-09-13
影响因子：
16.6
通讯作者：
Zhang, Haibing
中科院分区：
文献类型：
--
作者：
Zhang, Xixi;Zhang, Haiwei;Zhang, Haibing
RIPK 1的泛素化状态被认为是决定细胞命运的关键。然而，RIPK 1泛素化的体内作用仍然不确定。在这里，我们表明，表达RIPK 1（K）（376 R），这是在RIPK 1泛素化缺陷的小鼠在胚胎发育过程中死亡。这种致死性通过Fadd和Ripk 3或Mlkl的伴随缺失而完全挽救。从机制上讲，表达RIPK 1（K）（376 R）的细胞对TNF-α诱导的细胞凋亡和坏死性凋亡更敏感，复合物II形成更多，RIPK 1激活增加，这与RIPK 1（K376 R）（/）（K376 R）致死性通过RIPK 1激酶抑制剂治疗有效预防并通过缺失Infr 1挽救的观察结果一致。然而，Tnfr 1（-/-）Ripk 1（K）（376 R）（/）（K376 R）小鼠显示全身炎症并在2周内死亡。值得注意的是，这种致命的炎症是通过Ripk 3的缺失来拯救的。综上所述，这些发现揭示了Lys 376介导的RIPK 1泛素化在胚胎发生过程中抑制RIPK 1激酶活性依赖性致死途径和出生后RIPK 3依赖性炎症中的关键作用。
The ubiquitination status of RIPK1 is considered to be critical for cell fate determination. However, the in vivo role for RIPK1 ubiquitination remains undefined. Here we show that mice expressing RIPK1(K)(376R) which is defective in RIPK1 ubiquitination die during embryogenesis. This lethality is fully rescued by concomitant deletion of Fadd and Ripk3 or Mlkl. Mechanistically, cells expressing RIPK1(K)(376R) are more susceptible to TNF-alpha induced apoptosis and necroptosis with more complex II formation and increased RIPK1 activation, which is consistent with the observation that Ripk1(K376R)(/)(K376R) lethality is effectively prevented by treatment of RIPK1 kinase inhibitor and is rescued by deletion of Infr1. However, Tnfr1(-/-) Ripk1(K)(376R)(/)(K376R) mice display systemic inflammation and die within 2 weeks. Significantly, this lethal inflammation is rescued by deletion of Ripk3. Taken together, these findings reveal a critical role of Lys376-mediated ubiquitination of RIPK1 in suppressing RIPK1 kinase activity-dependent lethal pathways during embryogenesis and RIPK3-dependent inflammation postnatally.