Insufficiency of FZR1 disturbs HSC quiescence by inhibiting ubiquitin-dependent degradation of RUNX1 in aplastic anemia
Insufficiency of FZR1 disturbs HSC quiescence by inhibiting ubiquitin-dependent degradation of RUNX1 in aplastic anemia
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DOI：
10.1038/s41375-021-01445-5
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发表时间：
2021-10
期刊：
影响因子：
11.4
通讯作者：
Chengfang Zhou;Mei Kuang;Zhilong Liu;Xiaoqing Jia;Zhe Chen;Yuanyuan Liu;Zhigang Li;Weiru Wu;Le Ma;Jieping Chen;Yu Hou
中科院分区：
文献类型：
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作者：
Chengfang Zhou;Mei Kuang;Zhilong Liu;Xiaoqing Jia;Zhe Chen;Yuanyuan Liu;Zhigang Li;Weiru Wu;Le Ma;Jieping Chen;Yu Hou
FZR 1被认为是细胞周期和静止期的主要调节因子，但其在重型再生障碍性贫血（SAA）发病机制中的作用和分子机制尚不清楚。在这里，我们报告说，FZR 1下调SAA HSC与健康对照组相比，并与减少静止的HSC。Fzr 1单倍不足显示两种Fzr 1杂合子敲除小鼠模型中HSC的静止和自我更新能力受损。从机制上讲，FZR 1不足抑制了RUNX 1蛋白在赖氨酸125处的泛素化，导致RUNX 1蛋白的积累，这扰乱了SAA患者HSC的静止。此外，Runx 1的下调逆转了体内Fzr 1 +/− HSC的静止期丧失和长期自我更新能力受损，并在体外削弱了SAA患者BM的再增殖能力。因此，我们的研究结果提出了FZR 1-RUNX 1通路在SAA发病机制中通过HSC静止失调起决定性作用的可能性。
FZR1 has been implicated as a master regulator of the cell cycle and quiescence, but its roles and molecular mechanisms in the pathogenesis of severe aplastic anemia (SAA) are unclear. Here, we report that FZR1 is downregulated in SAA HSCs compared with healthy control and is associated with decreased quiescence of HSC. Haploinsufficiency ofFzr1shows impaired quiescence and self-renewal ability of HSC in twoFzr1heterozygous knockout mouse models. Mechanistically, FZR1 insufficiency inhibits the ubiquitination of RUNX1 protein at lysine 125, leading to the accumulation of RUNX1 protein, which disturbs the quiescence of HSCs in SAA patients. Moreover, downregulation of Runx1 reversed the loss of quiescence and impaired long-term self-renew ability inFzr1+/−HSCs in vivo and impaired repopulation capacity in BM from SAA patients in vitro. Our findings, therefore, raise the possibility of a decisive role of the FZR1-RUNX1 pathway in the pathogenesis of SAA via deregulation of HSC quiescence.