Vesicular formation regulated by ERK/MAPK pathway mediates human erythroblast enucleation.
Vesicular formation regulated by ERK/MAPK pathway mediates human erythroblast enucleation.
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ERK/MAPK通路调节的囊泡形成介导人成红细胞剜除
DOI：
10.1182/bloodadvances.2021004859
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发表时间：
2021-11-23
期刊：
影响因子：
7.5
通讯作者：
An X
中科院分区：
文献类型：
--
作者：
An C;Huang Y;Li M;Xue F;Nie D;Zhao H;Chen L;Yazdanbakhsh K;Sun L;Jiang Z;Mohandas N;An X
细胞外信号调节激酶（ERK）通路在人类正染性幼红细胞去核过程中发挥关键作用。ERK通过影响囊泡形成来调控人类幼红细胞的去核过程。
去核是哺乳动物红细胞生成过程中的一个关键事件，负责产生无核网织红细胞。尽管在对去核机制的理解方面取得了一定进展，但我们对去核机制的认识仍不完整。丝裂原活化蛋白激酶（MAPK）通路在生物过程中发挥多种作用，但其在红细胞生成中的作用尚未完全明确。对RNA测序数据的分析显示，在人类终末红细胞分化过程中，MAPK通路显著上调。MAPK通路由3个主要信号模块组成：MEK/ERK、p38和JNK。在本研究中，我们发现这3个模块中，只有ERK在晚期人类幼红细胞中显著上调。ERK表达增加及其磷酸化增强表明，ERK激活在去核过程中可能发挥作用。为了探究这一假设，我们用MEK/ERK抑制剂U0126处理分选后的人类正染性幼红细胞群体，发现U0126抑制了去核过程。相比之下，p38或JNK的抑制剂对去核没有影响。从机制上讲，U0126选择性地抑制了细胞质囊泡的形成/积累以及转铁蛋白受体的内吞作用，而不影响染色质浓缩、细胞核极化或核小体的形成。用诱导液泡形成的空泡素 - 1处理，可部分挽救U0126对去核的阻断作用。此外，磷酸化蛋白质组学分析显示，ERK通路失活导致内吞循环通路下调。综上所述，我们的研究结果揭示了ERK激活通过调节囊泡形成在人类幼红细胞去核过程中的新作用，这对于理解与去核缺陷相关的贫血具有重要意义。
ERK pathway plays a key role in enucleation of human orthochromatic erythroblasts. ERK regulates human erythroblast enucleation by affecting vesicular formation. Enucleation is a key event in mammalian erythropoiesis responsible for the generation of enucleated reticulocytes. Although progress is being made in developing mechanistic understanding of enucleation, our understanding of mechanisms for enucleation is still incomplete. The MAPK pathway plays diverse roles in biological processes, but its role in erythropoiesis has yet to be fully defined. Analysis of RNA-sequencing data revealed that the MAPK pathway is significantly upregulated during human terminal erythroid differentiation. The MAPK pathway consists of 3 major signaling cassettes: MEK/ERK, p38, and JNK. In the present study, we show that among these 3 cassettes, only ERK was significantly upregulated in late-stage human erythroblasts. The increased expression of ERK along with its increased phosphorylation suggests a potential role for ERK activation in enucleation. To explore this hypothesis, we treated sorted populations of human orthochromatic erythroblasts with the MEK/ERK inhibitor U0126 and found that U0126 inhibited enucleation. In contrast, inhibitors of either p38 or JNK had no effect on enucleation. Mechanistically, U0126 selectively inhibited formation/accumulation of cytoplasmic vesicles and endocytosis of the transferrin receptor without affecting chromatin condensation, nuclear polarization, or enucleosome formation. Treatment with vacuolin-1 that induces vacuole formation partially rescued the blockage of enucleation by U0126. Moreover, phosphoproteomic analysis revealed that inactivation of the ERK pathway led to downregulation of the endocytic recycling pathway. Collectively, our findings uncovered a novel role of ERK activation in human erythroblast enucleation by modulating vesicle formation and have implications for understanding anemia associated with defective enucleation.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
影响因子：
20.3
作者：
Jacobs-Helber, SM;Ryan, JJ;Sawyer, ST
通讯作者：
Sawyer, ST
影响因子：
6.5
作者：
Arcasoy, MO;Jiang, XH
通讯作者：
Jiang, XH
影响因子：
9.8
作者：
Dgany, O;Avidan, N;Tamary, H
通讯作者：
Tamary, H
影响因子：
20.3
作者：
Konstantinidis, Diamantis G.;Pushkaran, Suvarnamala;Kalfa, Theodosia A.
通讯作者：
Kalfa, Theodosia A.