Ribosomal protein RPL11 haploinsufficiency causes anemia in mice via activation of the RP-MDM2-p53 pathway.
Ribosomal protein RPL11 haploinsufficiency causes anemia in mice via activation of the RP-MDM2-p53 pathway.
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DOI：
10.1016/j.jbc.2022.102739
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发表时间：
2023-01
影响因子：
4.8
通讯作者：
Zhang, Yanping
中科院分区：
文献类型：
--
作者：
Franklin, Derek A.;Liu, Shijie;Jin, Aiwen;Cui, Pengfei;Guo, Zengli;Arend, Kyle C.;Moorman, Nathaniel J.;He, Shenghui;Wang, Gang Greg;Wan, Yisong Y.;Zhang, Yanping
最近发现的核糖体蛋白(RP)RPL11与MDM2的E3泛素连接酶功能相互作用并抑制其功能，建立了RP-MDM2-P53信号通路，该信号通路与包括核糖体生物发生、营养可获得性和代谢稳态在内的生物事件有关。RPS的突变导致一系列不同的表型，称为核糖体病，其中涉及P53的作用。在此，我们建立了RPL11条件性缺失的小鼠，以在体内研究Rp表达受损的影响及其与P53的功能联系。生殖细胞中一个Rpl11等位基因的缺失会导致胚胎死亡，而成年小鼠中一个Rpl11等位基因的缺失不会影响生存能力，而是会导致急性贫血。从机制上讲，我们发现RPL11单倍体不足激活了造血组织中的P53，并阻碍了红系前体的分化，导致红细胞发育不足。我们证明，通过删除一个p53等位基因来减少P53的剂量，可以挽救RPL11单倍体功能不全导致的红细胞前体分化抑制，并恢复小鼠的正常红细胞水平。此外，通过在MDM2中引入RP结合突变来阻断RP-MDM2-P53途径，可以防止RPL11单倍体功能不全导致的P53激活，并挽救小鼠的贫血。综上所述，这些发现表明，RP-MDM2-P53途径是RP动态平衡的关键检查点，而红系前体细胞周期受阻的P53依赖是通常与RP缺乏相关的贫血表型的分子基础。
Recent discovery of the ribosomal protein (RP) RPL11 interacting with and inhibiting the E3 ubiquitin ligase function of MDM2 established the RP-MDM2-p53 signaling pathway, which is linked to biological events, including ribosomal biogenesis, nutrient availability, and metabolic homeostasis. Mutations in RPs lead to a diverse array of phenotypes known as ribosomopathies in which the role of p53 is implicated. Here, we generated conditional RPL11-deletion mice to investigate in vivo effects of impaired RP expression and its functional connection with p53. While deletion of one Rpl11 allele in germ cells results in embryonic lethality, deletion of one Rpl11 allele in adult mice does not affect viability but leads to acute anemia. Mechanistically, we found RPL11 haploinsufficiency activates p53 in hematopoietic tissues and impedes erythroid precursor differentiation, resulting in insufficient red blood cell development. We demonstrated that reducing p53 dosage by deleting one p53 allele rescues RPL11 haploinsufficiency-induced inhibition of erythropoietic precursor differentiation and restores normal red blood cell levels in mice. Furthermore, blocking the RP-MDM2-p53 pathway by introducing an RP-binding mutation in MDM2 prevents RPL11 haploinsufficiency–caused p53 activation and rescues the anemia in mice. Together, these findings demonstrate that the RP-MDM2-p53 pathway is a critical checkpoint for RP homeostasis and that p53-dependent cell cycle arrest of erythroid precursors is the molecular basis for the anemia phenotype commonly associated with RP deficiency.
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影响因子：
50.3
作者：
Macias E;Jin A;Deisenroth C;Bhat K;Mao H;Lindström MS;Zhang Y
通讯作者：
Zhang Y
影响因子：
4.8
作者：
Dai, Mu-Shui;Challagundla, Kishore B.;Lu, Hua
通讯作者：
Lu, Hua
DOI：
10.1016/j.bbrc.2017.12.019
发表时间：
2018-01-08
影响因子：
3.1
作者：
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通讯作者：
Kenmochi, Naoya
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影响因子：
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作者：
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通讯作者：
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影响因子：
21.3
作者：
Grandori, C;Gomez-Roman, N;White, RJ
通讯作者：
White, RJ