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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Data availability
The authors declare that all data supporting the findings of this study are present in the paper and/or the Supplementary Materials. Additional data supporting the present study are available from the corresponding author upon reasonable request.
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Acknowledgements
We thank Dr. Xiaodong Wang (National Institute of Biological Sciences, Beijing, China) for providing Ripk3−/− mice, Dr. Jianke Zhang (Thomas Jefferson University, Philadelphia, PA, USA) for providing Fadd+/− mice, Dr. Feng Shao (National Institute of Biological Sciences, Beijing, China) for providing Tnfr1−/− mice and Dr. Qibin Leng (Institute Pasteur of Shanghai, Shanghai, China) for providing Ifnar−/− mice. We also thank Zhonghui Weng (Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences) for animal studies.
Funding
This work was supported by grants from the Strategic Priority Research Program of Chinese Academy of Sciences (Grant No. XDA26040306), the National Natural Science Foundation of China (31970688,31771537,82001684,81871101) and the National Key Research and Development Program of China (2018YFC1200201). ZCW was supported by “Chenguang Program” of Shanghai Education Development Foundation (19CG18) and Shanghai Rising Star Program of Science and Technology Commission of Shanghai Municipality (20QA1405600). We also thank support from Shanghai Frontiers Science Center of Cellular Homeostasis and Human Diseases, and GuangCi Professorship Program of Ruijin Hospital Shanghai Jiao Tong University School of Medicine.
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ML and HBZ designed the study; ML performed all experiments and analyzed data with assistance from JLL, MYX, XML, HWZ, XXW, LXW, YJO, XHW, XMZ, HL, QL, FL, WWR, JSD, XZW, and ZCW; YBL analyzed A20−/− Ripk3-/-Fadd-/- mice; CXX and QZ helped to analyze Abin1UBD/UBD mice; JBL, YL, YWZ, AKL, and QFL provided resources and intellectual input. ML and HBZ assembled figure panels and wrote the paper. HBZ supervised the project.
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Li, M., Liu, Y., Xu, C. et al. Ubiquitin-binding domain in ABIN1 is critical for regulating cell death and inflammation during development. Cell Death Differ 29, 2034–2045 (2022). https://doi.org/10.1038/s41418-022-00994-1
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DOI: https://doi.org/10.1038/s41418-022-00994-1
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