1. Academic Validation
  2. 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

  • Cell Death Differ. 2022 Oct;29(10):2034-2045. doi: 10.1038/s41418-022-00994-1.
Ming Li 1 Yongbo Liu 1 Chengxian Xu 1 Qun Zhao 1 Jianling Liu 1 Mingyan Xing 1 Xiaoming Li 1 Haiwei Zhang 1 Xiaoxia Wu 1 Lingxia Wang 1 Yangjing Ou 1 Xuanhui Wu 1 Xiaoming Zhao 1 Han Liu 1 Lin Qiu 1 Fang Li 2 Jinbao Li 2 Wuwei Rong 3 Yan Luo 4 Jiangshan Deng 5 Xiuzhe Wang 5 Zhichao Wang 6 Yuwu Zhao 5 Ankang Lv 3 Qingfeng Li 6 Haibing Zhang 7
Affiliations

Affiliations

  • 1 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 Department of Anesthesiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
  • 3 Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
  • 4 Department of Anesthesiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 5 Department of Neurology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 6 Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
  • 7 CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
Abstract

ABIN1 is a polyubiquitin-binding protein known to regulate NF-κB 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 (Abin1UBD/UBD) died during later embryogenesis owing to TNFR1-mediated cell death, similar to Abin1-/- mice. Abin1UBD/UBD cells were rendered sensitive to TNF-α-induced Apoptosis and Necroptosis as the inhibition of ABIN1UBD and A20 recruitment to the TNF-RSC complex leads to attenuated RIPK1 deubiquitination. Accordingly, the embryonic lethality of Abin1UBD/UBD mice was rescued via crossing with RIPK1 kinase-dead mice (Ripk1K45A/K45A) or the co-deletion of Ripk3 and one allele of Fadd, but not by the loss of Ripk3 or Mlkl alone. Unexpectedly, Abin1UBD/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 IKKε/TBK1 activation.

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