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, 200031, China.
Department of Anesthesiology, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, 200080, China.
Adv Sci (Weinh). 2024 Jan;11(3):e2303555. doi: 10.1002/advs.202303555. Epub 2023 Nov 27.
A20-binding inhibitor of NF-κB activation (ABIN1) is a polyubiquitin-binding protein that regulates cell death and immune responses. Although Abin1 is located on chromosome 5q in the region commonly deleted in patients with 5q minus syndrome, the most distinct of the myelodysplastic syndromes (MDSs), the precise role of ABIN1 in MDSs remains unknown. In this study, mice with a mutation disrupting the polyubiquitin-binding site (Abin1 ) is generated. These mice develop MDS-like diseases characterized by anemia, thrombocytopenia, and megakaryocyte dysplasia. Extramedullary hematopoiesis and bone marrow failure are also observed in Abin1 mice. Although Abin1 cells are sensitive to RIPK1 kinase-RIPK3-MLKL-dependent necroptosis, only anemia and splenomegaly are alleviated by RIPK3 deficiency but not by MLKL deficiency or the RIPK1 kinase-dead mutation. This indicates that the necroptosis-independent function of RIPK3 is critical for anemia development in Abin1 mice. Notably, Abin1 mice exhibit higher levels of type I interferon (IFN-I) expression in bone marrow cells compared towild-type mice. Consistently, blocking type I IFN signaling through the co-deletion of Ifnar1 greatly ameliorated anemia, thrombocytopenia, and splenomegaly in Abin1 mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.
NF-κB 激活的 A20 结合抑制剂（ABIN1）是一种多泛素结合蛋白，可调节细胞死亡和免疫反应。尽管 Abin1 位于 5q 染色体上，是患有 5q 缺失综合征（骨髓增生异常综合征中最明显的一种）患者中常见缺失的区域，但 ABIN1 在 MDS 中的精确作用仍不清楚。在这项研究中，生成了一种突变破坏多泛素结合位点（Abin1）的小鼠。这些小鼠发展为 MDS 样疾病，表现为贫血、血小板减少和巨核细胞发育不良。也观察到 Abin1 小鼠骨髓外造血和骨髓衰竭。虽然 Abin1 细胞对 RIPK1 激酶-RIPK3-MLKL 依赖性细胞坏死敏感，但只有 RIPK3 缺陷而非 MLKL 缺陷或 RIPK1 激酶失活突变可缓解贫血和脾肿大。这表明 RIPK3 的坏死非依赖性功能对于 Abin1 小鼠贫血的发展至关重要。值得注意的是，与野生型小鼠相比，Abin1 小鼠的骨髓细胞中 I 型干扰素（IFN-I）表达水平更高。一致地，通过 Ifnar1 的共缺失阻断 I 型 IFN 信号显著改善了 Abin1 小鼠的贫血、血小板减少和脾肿大。总之，这些结果表明 ABIN1(Q478) 通过调节 I 型 IFN 表达防止造血缺陷的发展。
