ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression.
ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression.
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DOI：
10.1002/advs.202303555
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发表时间：
2024-01
期刊：
影响因子：
15.1
通讯作者：
Zhang, Haibing
中科院分区：
文献类型：
--
作者：
Wu, Xuanhui;Wang, Yong;Chen, Bingyi;Liu, Yongbo;Li, Fang;Ou, Yangjing;Zhang, Haiwei;Wu, Xiaoxia;Li, Xiaoming;Wang, Lingxia;Rong, Wuwei;Liu, Jianling;Xing, Mingyan;Zhao, Xiaoming;Liu, Han;Ge, Lingling;Lv, Ankang;Wang, Lan;Wang, Zhichao;Li, Ming;Zhang, Haibing
A20结合的核因子κB激活抑制因子(ABIN1)是一种多泛素结合蛋白，调节细胞死亡和免疫反应。尽管ABIN1位于5q-综合征患者中常见的缺失区域，但ABIN1在MDS中的确切作用仍不清楚。在这项研究中，产生了突变破坏多泛素结合位点(Abin1Q478H/Q478H)的小鼠。这些小鼠患上类似MDS的疾病，以贫血、血小板减少和巨核细胞发育不良为特征。在Abin1Q478H/Q478H小鼠中也观察到髓外造血和骨髓衰竭。虽然Abin1Q478H/Q478H细胞对RIPK1-RIPK3-MLKL依赖的坏死性下垂敏感，但RIPK3缺乏只能缓解贫血和脾肿大，而MLKL缺乏或RIPK1激酶死亡突变不能缓解贫血和脾肿大。这表明RIPK3的非坏死下垂功能在Abin1Q478H/Q478H小鼠贫血的发生中起关键作用。值得注意的是，Abin1Q478H/Q478H小鼠的骨髓细胞中I型干扰素(IFN-I)的表达水平高于ild类型的小鼠。一致地，通过Ifnar1的共缺失来阻断I型干扰素信号显著改善了Abin1Q478H/Q478H小鼠的贫血、血小板减少和脾肿大。综上所述，这些结果表明ABIN1(Q478)通过调节I型干扰素的表达来预防造血缺陷的发生。在ABIN1多泛素结合区表达Q478H突变的小鼠(Abin1Q478H/Q478H小鼠)表现出MDS样疾病，包括贫血、血小板减少和巨核细胞异常增殖症。不依赖于坏死下垂的RIPK3功能有助于贫血，而Ifnar1的共同缺失可以挽救贫血、血小板减少和脾肿大，突出表明ABIN1(Q478)通过I型干扰素的表达作为造血缺陷的调节因子。
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 (Abin1Q478H/Q478H ) 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 Abin1Q478H/Q478H mice. Although Abin1Q478H/Q478H 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 Abin1Q478H/Q478H mice. Notably, Abin1Q478H/Q478H 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 Abin1Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression. The mice expressing the Q478H mutation in the polyubiquitin‐binding domain of ABIN1 (Abin1Q478H/Q478H mice) exhibit MDS‐like diseases, including anemia, thrombocytopenia, and megakaryocyte dysplasia. Necroptosis‐independent RIPK3 function contributes to anemia, while co‐deletion of Ifnar1 rescues anemia, thrombocytopenia, and splenomegaly, highlighting ABIN1 (Q478) as a regulator of hematopoietic deficiencies through type I IFN expression.
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