Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Neurobiology Section, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Neuron. 2019 Oct 23;104(2):290-304.e8. doi: 10.1016/j.neuron.2019.07.004. Epub 2019 Aug 1.
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.
液-液相分离是含有朊样结构域（PrLDs）的蛋白质的一种新兴特性，但其在体内的分离作用仍知之甚少。TIA 蛋白含有 C 端 PrLD，PrLD 中的突变与多种疾病有关。在这里，我们表明秀丽隐杆线虫 TIAR-2/TIA 蛋白具有自主细胞功能，可抑制轴突再生。TIAR-2 在体外发生液-液相分离，并在体内形成具有液态特性的颗粒。轴突损伤诱导 TIAR-2 颗粒数量的短暂增加。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抑制再生很重要。TIAR-2 在体内也被丝氨酸磷酸化。不可磷酸化的 TIAR-2 变体不能形成颗粒，也不能抑制轴突再生。我们的数据证明了 TIAR-2 的体内相分离功能，并确定了其在轴突再生中的功能的关键特征。
