<br>ABIN1 (Q478) 是通过调节 I 型 IFN 表达来预防造血缺陷所必需的,Advanced Science

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ABIN1 (Q478) 是通过调节 I 型 IFN 表达来预防造血缺陷所必需的
Advanced Science ( IF 14.3 ) Pub Date : 2023-11-27 , DOI: 10.1002/advs.202303555
Xuanhui Wu ₁ , Yong Wang ₁ , Bingyi Chen ₁ , Yongbo Liu ₁ , Fang Li ₂ , Yangjing Ou ₁ , Haiwei Zhang ₁ , Xiaoxia Wu ₁ , Xiaoming Li ₁ , Lingxia Wang ₁ , Wuwei Rong ₃ , Jianling Liu ₁ , Mingyan Xing ₁ , Xiaoming Zhao ₁ , Han Liu ₁ , Lingling Ge ₄ , Ankang Lv ₃ , Lan Wang ₁ , Zhichao Wang ₄ , Ming Li ₁ , Haibing Zhang ₁

Affiliation

NF-κB 激活的 A20 结合抑制剂 (ABIN1) 是一种多聚泛素结合蛋白，可调节细胞死亡和免疫反应。尽管Abin1位于 5q 染色体上，该区域通常在 5q 负综合征（最明显的骨髓增生异常综合征 (MDS)）患者中缺失，但 ABIN1 在 MDS 中的确切作用仍不清楚。在本研究中，产生了具有破坏多聚泛素结合位点 ( Abin1 ^Q478H/Q478H ) 突变的小鼠。这些小鼠出现以贫血、血小板减少和巨核细胞发育不良为特征的MDS样疾病。在Abin1 ^Q478H/Q478H小鼠中也观察到髓外造血和骨髓衰竭。尽管Abin1 ^Q478H/Q478H细胞对 RIPK1 激酶-RIPK3-MLKL 依赖性坏死性凋亡敏感，但 RIPK3 缺陷仅可减轻贫血和脾肿大，而 MLKL 缺陷或 RIPK1 激酶死亡突变则不能减轻贫血和脾肿大。这表明 RIPK3 的独立于坏死性凋亡的功能对于Abin1 ^Q478H/Q478H小鼠贫血的发生至关重要。值得注意的是，与野生型小鼠相比，Abin1 ^Q478H/Q478H小鼠在骨髓细胞中表现出更高水平的 I 型干扰素 (IFN-I) 表达。一致地，通过共同删除Ifnar1来阻断 I 型 IFN 信号传导可极大改善Abin1 ^Q478H/Q478H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 表达来预防造血缺陷的发生。

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ABIN1 (Q478) is Required to Prevent Hematopoietic Deficiencies through Regulating Type I IFNs Expression

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^Q478H/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 Abin1^Q478H/Q478H mice. Although Abin1^Q478H/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 Abin1^Q478H/Q478H mice. Notably, Abin1^Q478H/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 Abin1^Q478H/Q478H mice. Together, these results demonstrates that ABIN1(Q478) prevents the development of hematopoietic deficiencies by regulating type I IFN expression.

更新日期：2023-11-27

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