a Department of Biomedical Sciences and Mari Lowe Center for Comparative Oncology , School of Veterinary Medicine, University of Pennsylvania , Philadelphia , PA , USA.
b Division of Hematology , Children's Hospital of Philadelphia, Perelman School of Medicine , Philadelphia , PA , USA.
Cancer Biol Ther. 2017 Jul 3;18(7):534-543. doi: 10.1080/15384047.2017.1345395. Epub 2017 Jul 5.
Recent studies demonstrated that prolonged exposure of haematopoietic stem cells (HSCs) to type I interferons (IFN) stimulates HSCs entrance into cell cycle, continuous proliferation and eventual exhaustion, which could be prevented by ablation of the Ifnar1 chain of IFN receptor. Given that levels IFNAR1 expression can be robustly affected by IFN-independent ubiquitination and downregulation of IFNAR1 in response to activation of protein kinases such as protein kinase R-like endoplasmic reticulum kinase (PERK) and casein kinase 1α (CK1α), we aimed to determine the role of IFNAR1 downregulation in the maintenance of HSCs. Mice harboring the ubiquitination-deficient Ifnar1 allele displayed greater levels of haematopoietic cell progenitors but reduced numbers of the long-term HSCs compared with wild type mice and animals lacking Ifnar1. Studies using competitive bone marrow repopulation assays showed that CK1α (but not PERK) is essential for the long-term HSCs function. Concurrent ablation of Ifnar1 led to a modest attenuation of the CK1α-null phenotype indicating that, although other CK1α targets are likely to be important, IFNAR1 downregulation can contribute to the maintenance of the HSCs function.
最近的研究表明，造血干细胞（HSCs）长时间暴露于 I 型干扰素（IFN）中会刺激 HSCs 进入细胞周期，持续增殖，最终衰竭，而这种衰竭可以通过消除 IFN 受体的 Ifnar1 链来预防。鉴于 IFN 独立的泛素化作用和 IFNAR1 的下调可以显著影响 IFNAR1 的表达水平，这种下调是对蛋白激酶（如蛋白激酶 R 样内质网激酶（PERK）和酪蛋白激酶 1α（CK1α）的激活的反应，我们旨在确定 IFNAR1 下调在维持 HSCs 中的作用。与野生型小鼠和缺乏 Ifnar1 的动物相比，携带泛素化缺陷型 Ifnar1 等位基因的小鼠具有更高水平的造血细胞祖细胞，但长期 HSCs 的数量减少。使用竞争骨髓重编程测定的研究表明，CK1α（而非 PERK）对于长期 HSCs 的功能是必需的。同时消除 Ifnar1 导致 CK1α 缺失表型的适度衰减表明，尽管其他 CK1α 靶标可能很重要，但 IFNAR1 的下调有助于维持 HSCs 的功能。
