mRNA transport in neurons requires formation of transport granules containing many protein components, and subsequent alterations in phosphorylation status can release transcripts for translation. Further, mutations in a structurally disordered domain of the transport granule protein hnRNPA2 increase its aggregation and cause hereditary proteinopathy of neurons, myocytes, and bone. We examine in vitro hnRNPA2 granule component phase separation, partitioning specificity, assembly/disassembly, and the link to neurodegeneration. Transport granule components hnRNPF and ch‐TOG interact weakly with hnRNPA2 yet partition specifically into liquid phase droplets with the low complexity domain (LC) of hnRNPA2, but not FUS LC. In vitro hnRNPA2 tyrosine phosphorylation reduces hnRNPA2 phase separation, prevents partitioning of hnRNPF and ch‐TOG into hnRNPA2 LC droplets, and decreases aggregation of hnRNPA2 disease variants. The expression of chimeric hnRNPA2 D290V in Caenorhabditis elegans results in stress‐induced glutamatergic neurodegeneration; this neurodegeneration is rescued by loss of tdp‐1, suggesting gain‐of‐function toxicity. The expression of Fyn, a tyrosine kinase that phosphorylates hnRNPA2, reduces neurodegeneration associated with chimeric hnRNPA2 D290V. These data suggest a model where phosphorylation alters LC interaction specificity, aggregation, and toxicity.

中文翻译：

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酪氨酸磷酸化调节 hnRNPA2 颗粒蛋白分配并减少神经变性

神经元中的 mRNA 转运需要形成包含许多蛋白质成分的转运颗粒，随后磷酸化状态的改变可以释放转录本进行翻译。此外，转运颗粒蛋白 hnRNPA2 结构无序域中的突变会增加其聚集并导致神经元、肌细胞和骨骼的遗传性蛋白质病。我们检查了体外hnRNPA2 颗粒组分相分离、分区特异性、组装/拆卸以及与神经变性的联系。运输颗粒成分 hnRNPF 和 ch-TOG 与 hnRNPA2 的相互作用较弱，但会特异性地划分为具有 hnRNPA2 的低复杂性域 (LC) 的液相液滴，但不是 FUS LC。体外hnRNPA2 酪氨酸磷酸化减少 hnRNPA2 相分离，防止 hnRNPF 和 ch-TOG 分配到 hnRNPA2 LC 液滴中，并减少 hnRNPA2 疾病变体的聚集。嵌合 hnRNPA2 D290V 在秀丽隐杆线虫中的表达导致应激诱导的谷氨酸能神经变性；这种神经变性通过tdp-1的丢失而被挽救，表明功能获得性毒性。Fyn（一种磷酸化 hnRNPA2 的酪氨酸激酶）的表达减少了与嵌合 hnRNPA2 D290V 相关的神经变性。这些数据表明了一个模型，其中磷酸化改变了 LC 相互作用的特异性、聚集和毒性。