Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation
Role of the novel endoribonuclease SLFN14 and its disease-causing mutations in ribosomal degradation
复制标题
DOI：
10.1261/rna.066415.118
复制
发表时间：
2018-07-01
期刊：
影响因子：
4.5
通讯作者：
Pisarev, Andrey, V
中科院分区：
文献类型：
--
作者：
Fletcher, Sarah J.;Pisareva, Vera P.;Pisarev, Andrey, V
血小板是血流中无核且大多无核糖体的细胞，源自骨髓内的巨核细胞，对于受伤部位的止血至关重要。遗传性血小板减少症是一组以血小板计数低为特征的疾病，通常与出血过多有关。 SLFN14 是最近发现的与遗传性血小板减少症相关的基因之一，其中 SLFN14 中的几个杂合错义突变被确定会导致巨核细胞成熟缺陷和血小板功能障碍。然而，SLFN14 最近被描述为一种核糖体相关蛋白，导致兔网织红细胞中 rRNA 和核糖体结合的 mRNA 降解。为了揭示 SLFN14 的细胞功能以及 SLFN14 与血小板减少症之间的联系，我们在体外模型中检查了 SLFN14（WT/突变体）。在这里，我们表明所有 SLFN14 变体与核糖体共定位并介导 rRNA 核酸内切降解。与 SLFN14 WT 相比，由于蛋白质部分错误折叠导致翻译后降解，突变体的表达显着降低。此外，所有 SLFN14 变体都倾向于形成寡聚体。这些发现可以解释杂合突变对患者血小板中 SLFN14 表达的显性负面影响。总的来说，我们认为 SLFN14 可能参与血小板形成和成熟过程中的核糖体降解。
Platelets are anucleate and mostly ribosome-free cells within the bloodstream, derived from megakaryocytes within bone marrow and crucial for cessation of bleeding at sites of injury. Inherited thrombocytopenias are a group of disorders characterized by a low platelet count and are frequently associated with excessive bleeding. SLFN14 is one of the most recently discovered genes linked to inherited thrombocytopenia where several heterozygous missense mutations in SLFN14 were identified to cause defective megakaryocyte maturation and platelet dysfunction. Yet, SLFN14 was recently described as a ribosome-associated protein resulting in rRNA and ribosome-bound mRNA degradation in rabbit reticulocytes. To unveil the cellular function of SLFN14 and the link between SLFN14 and thrombocytopenia, we examined SLFN14 (WT/mutants) in in vitro models. Here, we show that all SLFN14 variants colocalize with ribosomes and mediate rRNA endonucleolytic degradation. Compared to SLFN14 WT, expression of mutants is dramatically reduced as a result of post-translational degradation due to partial misfolding of the protein. Moreover, all SLFN14 variants tend to form oligomers. These findings could explain the dominant negative effect of heterozygous mutation on SLFN14 expression in patients' platelets. Overall, we suggest that SLFN14 could be involved in ribosome degradation during platelet formation and maturation.