OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy
OGT Regulates Hematopoietic Stem Cell Maintenance via PINK1-Dependent Mitophagy
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DOI：
10.1016/j.celrep.2020.108579
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发表时间：
2021-01-05
期刊：
影响因子：
8.8
通讯作者：
Nakajima, Hideaki
中科院分区：
文献类型：
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作者：
Murakami, Koichi;Kurotaki, Daisuke;Nakajima, Hideaki
O-连接的N-乙酰葡萄糖胺（O-GlcNAc）转移酶（OGT）是一种独特的将O-GlcNAc引入靶蛋白的酶，它在不同的细胞类型中关键地调节各种细胞过程。然而，它在造血干细胞和祖细胞（HSPCs）中的作用仍然难以捉摸。在这里，使用OGT条件性基因敲除小鼠，我们表明，OGT是必不可少的HSPCs。Ogt在HSPCs中高度表达，其破坏诱导HSPCs的快速损失，并增加活性氧和凋亡。特别地，Ogt缺陷型造血干细胞（HSC）失去静止，不能在体内维持，并且变得易受再生和竞争应激的影响。有趣的是，Ogt缺陷型HSC通过H3 K4 me 3的失调，由于线粒体自噬受损，关键的线粒体自噬调节因子Pink 1降低，从而积累有缺陷的线粒体。此外，PINK 1的过表达恢复了线粒体自噬和Ogt缺陷型HSC的数量。总的来说，我们的研究结果表明，OGT通过PINK 1依赖性线粒体自噬确保线粒体质量，从而严格调节HSC的维持和应激反应。
O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogtdeficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.