Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development
Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development
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DOI：
10.1038/s41418-022-00994-1
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发表时间：
2022-04-16
影响因子：
12.4
通讯作者：
Zhang, Haibing
中科院分区：
文献类型：
--
作者：
Li, Ming;Liu, Yongbo;Zhang, Haibing
ABIN 1是已知调节NF-κ B活化和细胞死亡信号传导的多聚泛素结合蛋白。Abin 1基因突变可导致严重的人类免疫性疾病，如银屑病、系统性红斑狼疮和系统性硬化症。在这里，我们产生了破坏ABIN 1（Abin 1（UBD/UBD））的泛素结合结构域的小鼠，这些小鼠在后来的胚胎发育过程中由于TNFR 1介导的细胞死亡而死亡，类似于Abin 1（-/-）小鼠。由于ABIN 1（UBD）和A20募集至TNF-RSC复合物的抑制导致减弱的RIPK 1去泛素化，因此使ABIN 1（UBD/UBD）细胞对TNF-α诱导的凋亡和坏死性凋亡敏感。因此，Abin 1（UBD/UBD）小鼠的胚胎致死性通过与RIPK 1激酶死亡小鼠（Ripk 1（K45 A/K45 A））杂交或Ripk 3和Fadd的一个等位基因的共缺失而得到挽救，但不能通过Ripk 3或Mlk 1单独的缺失而得到挽救。出乎意料的是，具有Ripk 3和两个Fadd等位基因的共缺失的Abinl（UBD/UBD）小鼠在E14.5死亡。这种死亡是由自发性RIPK 1泛素化依赖性多种炎性细胞因子过度产生引起的，可以通过Ripk 1或Tnfr 1与Ifnar联合共缺失来挽救。总的来说，这些数据证明了介导ABIN 1-A20轴的ABIN 1 UBD结构域在胚胎发育期间限制RIPK 1激活依赖性细胞死亡的重要性。此外，我们的研究结果揭示了一个以前未被重视的泛素途径，它通过FADD/Casp 8调节RIPK 1泛素化，抑制自发的IKK β 1/TBK 1激活。
ABIN1 is a polyubiquitin-binding protein known to regulate NF-kappa B activation and cell death signaling. Mutations in Abin1 can cause severe immune diseases in human, such as psoriasis, systemic lupus erythematosus, and systemic sclerosis. Here, we generated mice that disrupted the ubiquitin-binding domain of ABIN1 (Abin1(UBD/UBD)) died during later embryogenesis owing to TNFR1-mediated cell death, similar to Abin1(-/-) mice. Abin1(UBD/UBD) cells were rendered sensitive to TNF-alpha-induced apoptosis and necroptosis as the inhibition of ABIN1(UBD) and A20 recruitment to the TNF-RSC complex leads to attenuated RIPK1 deubiquitination. Accordingly, the embryonic lethality of Abin1(UBD/UBD) mice was rescued via crossing with RIPK1 kinase-dead mice (Ripk1(K45A/K45A)) or the co-deletion of Ripk3 and one allele of Fadd, but not by the loss of Ripk3 or Mlkl alone. Unexpectedly, Abin1(UBD/UBD) mice with the co-deletion of Ripk3 and both Fadd alleles died at E14.5. This death was caused by spontaneous RIPK1 ubiquitination-dependent multiple inflammatory cytokines over production and could be rescued by the co-deletion of Ripk1 or Tnfr1 combined with Ifnar. Collectively, these data demonstrate the importance of the ABIN1 UBD domain, which mediates the ABIN1-A20 axis, at limiting RIPK1 activation-dependent cell death during embryonic development. Furthermore, our findings reveal a previously unappreciated ubiquitin pathway that regulates RIPK1 ubiquitination by FADD/Casp8 to suppress spontaneous IKK epsilon/TBK1 activation.