Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules
Inhibition of Axon Regeneration by Liquid-like TIAR-2 Granules
复制标题
DOI：
10.1016/j.neuron.2019.07.004
复制
发表时间：
2019-10-23
期刊：
影响因子：
16.2
通讯作者：
Jin, Yishi
中科院分区：
文献类型：
--
作者：
Andrusiak, Matthew G.;Sharifnia, Panid;Jin, Yishi
相分离成液体样区室是含有朊病毒样结构域 (PrLD) 的蛋白质的一个新兴特性，但相分离的体内作用仍然知之甚少。 TIA 蛋白含有 C 末端 PrLD，PrLD 的突变与多种疾病相关。在这里，我们展示了线虫 TIAR-2/TIA 蛋白自主地发挥细胞功能来抑制轴突再生。 TIAR-2在体外经历液-液相分离，并在体内形成具有液体性质的颗粒。轴突损伤导致 TIAR-2 颗粒数量短暂增加。 PrLD 对于颗粒形成和抑制再生是必要且充分的。 PrLD 内的酪氨酸残基对于颗粒形成和再生抑制很重要。 TIAR-2 在体内也被丝氨酸磷酸化。不可磷酸化的 TIAR-2 变体不会形成颗粒，并且无法抑制轴突再生。我们的数据证明了相分离 TIAR-2 的体内功能，并确定了对其轴突再生功能至关重要的特征。
Phase separation into liquid-like compartments is an emerging property of proteins containing prion-like domains (PrLDs), yet the in vivo roles of phase separation remain poorly understood. TIA proteins contain a C-terminal PrLD, and mutations in the PrLD are associated with several diseases. Here, we show that the C. elegans TIAR-2/TIA protein functions cell autonomously to inhibit axon regeneration. TIAR-2 undergoes liquid-liquid phase separation in vitro and forms granules with liquid-like properties in vivo. Axon injury induces a transient increase in TIAR-2 granule number. The PrLD is necessary and sufficient for granule formation and inhibiting regeneration. Tyrosine residues within the PrLD are important for granule formation and inhibition of regeneration. TIAR-2 is also serine phosphorylated in vivo. Non-phosphorylatable TIAR-2 variants do not form granules and are unable to inhibit axon regeneration. Our data demonstrate an in vivo function for phase-separated TIAR-2 and identify features critical for its function in axon regeneration.