Functional requirements for a Samd14-capping protein complex in stress erythropoiesis.
Functional requirements for a Samd14-capping protein complex in stress erythropoiesis.
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应激红细胞生成中对Samd 14-加帽蛋白复合物的功能要求。
DOI：
10.7554/elife.76497
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发表时间：
2022-06-17
期刊：
影响因子：
7.7
通讯作者：
Hewitt, Kyle J.
中科院分区：
文献类型：
--
作者：
Ray, Suhita;Chee, Linda;Zhou, Yichao;Schaefer, Meg A.;Naldrett, Michael J.;Alvarez, Sophie;Woods, Nicholas T.;Hewitt, Kyle J.
急性贫血诱导红系前体细胞快速扩增和加速分化以补充红细胞。旁分泌信号-包括干细胞因子（SCF）/Kit信号和其他信号输入之间的合作-是贫血中红细胞前体活性增加所必需的。我们先前的工作揭示了不育α基序（SAM）结构域14（Samd 14）基因在小鼠遗传模型中增加了红系系统的再生能力，并促进了应激依赖性Kit信号传导。然而，Samd 14在应激红细胞生成中的作用机制尚不清楚。我们鉴定了Samd 14与F-肌动蛋白加帽蛋白（CP）复合物的α-和β-异二聚体之间的蛋白质-蛋白质相互作用。CP β亚基的敲低增加了小鼠离体培养物中的红系成熟，并降低了应激红系前体细胞的集落形成潜力。在Samd 14活性的遗传互补测定中，我们的结果显示，Samd 14-CP相互作用是红系前体细胞水平和功能的决定因素。Samd 14-CP促进CD 71介导的脾红系前体细胞中的SCF/Kit信号传导。鉴于Kit信号在造血中的作用和Samd 14在Kit途径活化中的作用，该机制可能在急性/慢性贫血中具有病理学意义。贫血是一种身体缺乏健康的红细胞来携带足够的氧气来支持其器官的情况。已知一系列因素会导致贫血，包括创伤性失血、毒素或营养缺乏。据估计，三分之一的育龄妇女患有贫血症，这可能导致疲劳、虚弱和呼吸急促。严重的贫血促使激素和生长因子的释放，导致前体红细胞的快速再生，以补充血液中的供应。为了了解红细胞再生是如何被控制的，Ray等人研究了与再生血液有关的蛋白质，这些蛋白质是用化学物质诱导贫血的小鼠。先前的研究表明，蛋白质Samd 14在贫血患者中的产量较高，并且与丢失的红细胞的恢复有关。然而，目前尚不清楚Samd 14蛋白如何在再生血细胞中发挥作用，或者Samd 14是否与红细胞生成所需的其他蛋白相互作用。为了阐明这些问题，暴露于贫血条件下的小鼠细胞被用来观察Samd 14与哪些蛋白质结合。纯化的Samd 14显示其与肌动蛋白帽蛋白相互作用。这种相互作用依赖于Samd 14的特定区域，该区域与结合帽蛋白的其他蛋白质中的区域相似。Ray等人发现，Samd 14和肌动蛋白帽蛋白之间的相互作用增加了新红细胞发育和存活所需的信号。这些结果确定了一种信号机制，如果被破坏，可能会导致贫血的发展。他们导致更好地了解我们的身体如何从贫血中恢复，以及治疗这种疾病的潜在途径。
Acute anemia induces rapid expansion of erythroid precursors and accelerated differentiation to replenish erythrocytes. Paracrine signals—involving cooperation between stem cell factor (SCF)/Kit signaling and other signaling inputs—are required for the increased erythroid precursor activity in anemia. Our prior work revealed that the sterile alpha motif (SAM) domain 14 (Samd14) gene increases the regenerative capacity of the erythroid system in a mouse genetic model and promotes stress-dependent Kit signaling. However, the mechanism underlying Samd14’s role in stress erythropoiesis is unknown. We identified a protein-protein interaction between Samd14 and the α- and β-heterodimers of the F-actin capping protein (CP) complex. Knockdown of the CP β subunit increased erythroid maturation in murine ex vivo cultures and decreased colony forming potential of stress erythroid precursors. In a genetic complementation assay for Samd14 activity, our results revealed that the Samd14-CP interaction is a determinant of erythroid precursor cell levels and function. Samd14-CP promotes SCF/Kit signaling in CD71med spleen erythroid precursors. Given the roles of Kit signaling in hematopoiesis and Samd14 in Kit pathway activation, this mechanism may have pathological implications in acute/chronic anemia. Anemia is a condition in which the body has a shortage of healthy red blood cells to carry enough oxygen to support its organs. A range of factors are known to cause anemia, including traumatic blood loss, toxins or nutritional deficiency. An estimated one-third of all women of reproductive age are anemic, which can cause tiredness, weakness and shortness of breath. Severe anemia drives the release of hormones and growth factors, leading to a rapid regeneration of precursor red blood cells to replenish the supply in the blood. To understand how red blood cell regeneration is controlled, Ray et al. studied proteins involved in regenerating blood using mice in which anemia had been induced with chemicals. Previous research had shown that the protein Samd14 is produced at higher quantities in individuals with anemia, and is involved with the recovery of lost red blood cells. However, it is not known how the Samd14 protein plays a role in regenerating blood cells, or whether Samd14 interacts with other proteins required for red blood cell production. To shed light on these questions, mouse cells exposed to anemia conditions were used to see what proteins Samd14 binds to. Purifying Samd14 revealed that it interacts with the actin capping protein. This interaction relies on a specific region of Samd14 that is similar to regions in other proteins that bind capping proteins. Ray et al. found that the interaction between Samd14 and the actin capping protein increased the signals needed for the development and survival of new red blood cells. These results identify a signaling mechanism that, if disrupted, could cause anemia to develop. They lead to a better understanding of how our bodies recover from anemia, and potential avenues to treat this condition.