Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia
Mutations in the cofilin partner Aip1/Wdr1 cause autoinflammatory disease and macrothrombocytopenia
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DOI：
10.1182/blood-2006-10-055087
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发表时间：
2007-10-01
期刊：
影响因子：
20.3
通讯作者：
Justice, Monica J.
中科院分区：
文献类型：
--
作者：
Kile, Benjamin T.;Panopoulos, Athanasia D.;Justice, Monica J.
肌动蛋白动力学的一个关键介质是蛋白质cofilin，它促进细丝切断和解聚，促进现有细丝的分解，并增强新产生的倒刺末端的细丝生长。它与肌动蛋白相互作用蛋白1（Alp 1）一起起作用，后者有助于加速cofilin的活性。虽然在了解其生化功能方面取得了进展，但cofilin/Aip 1复合物调节的生理过程，特别是在高等生物中，尚未确定。我们已经产生了一个等位基因系列WD 40重复蛋白1（WDR 1），哺乳动物同源AIP 1，并报告说，减少WDR 1功能产生了显着的表型梯度。虽然Wdr 1基因座功能的严重丧失会导致胚胎死亡，但携带亚型等位基因的小鼠会发生巨血小板减少症和自身炎症性疾病。巨血小板减少症是巨核细胞成熟缺陷的结果，其导致正常血小板脱落失败。自身炎性疾病是骨髓源性但非淋巴源性的，其特征在于中性粒细胞大量浸润到炎性病变中。Wdr 1突变中性粒细胞的细胞骨架反应受损。这些研究确立了巨核细胞和中性粒细胞对Wdr 1的基本要求，表明cofilin介导的肌动蛋白动力学对这两种细胞类型的发育和功能至关重要。
A pivotal mediator of actin dynamics is the protein cofilin, which promotes filament severing and depolymerization, facilitating the breakdown of existing filaments, and the enhancement of filament growth from newly created barbed ends. It does so in concert with actin interacting protein 1 (Alp1), which serves to accelerate cofilin's activity. While progress has been made in understanding its biochemical functions, the physiologic processes the cofilin/Aip1 complex regulates, particularly in higher organisms, are yet to be determined. We have generated an allelic series for WD40 repeat protein 1 (Wdr1), the mammalian homolog of Aip1, and report that reductions in Wdr1 function produce a dramatic phenotype gradient. While severe loss of function at the Wdr1 locus causes embryonic lethality, macrothrombocytopenia and autoinflammatory disease develop in mice carrying hypomorphic alleles. Macrothrombocytopenia is the result of megakaryocyte maturation defects, which lead to a failure of normal platelet shedding. Autoinflammatory disease, which is bone marrow derived yet nonlymphoid in origin, is characterized by a massive infiltration of neutrophils into inflammatory lesions. Cytoskeletal responses are impaired in Wdr1 mutant neutrophils. These studies establish an essential requirement for Wdr1 in megakaryocytes and neutrophils, indicating that cofilin-mediated actin dynamics are critically important to the development and function of both cell types.