TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.
TIA1 potentiates tau phase separation and promotes generation of toxic oligomeric tau.
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DOI：
10.1073/pnas.2014188118
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发表时间：
2021-03-02
影响因子：
11.1
通讯作者：
Wolozin B
中科院分区：
文献类型：
--
作者：
Ash PEA;Lei S;Shattuck J;Boudeau S;Carlomagno Y;Medalla M;Mashimo BL;Socorro G;Al-Mohanna LFA;Jiang L;Öztürk MM;Knobel M;Ivanov P;Petrucelli L;Wegmann S;Kanaan NM;Wolozin B
蛋白质的相分离越来越被认为在生物过程中发挥着重要作用。最近的研究表明，tau蛋白相分离，但生物学意义是未知的，因为通常使用人工拥挤剂，所得的tau是无毒的。我们现在证明，TIA 1增强了RNA介导的tau相分离，从而实现了在生理浓度下发生的过程，并且还指导了具有生物活性、高神经毒性的寡聚tau的形成。功能相关蛋白质的协调相分离提供了无膜细胞器可以指导生物活性的一般机制。Tau蛋白在应激颗粒的生物学和神经元的应激反应中起着重要作用，但这些生化相互作用的性质尚不清楚。在这里，我们表明，tau与RNA和RNA结合蛋白TIA1的相互作用足以在生理浓度下驱动tau的相分离，而不需要人工拥挤剂，如聚乙二醇（PEG）。我们进一步表明，在RNA和TIA1的存在下，tau的相分离产生丰富的tau寡聚体。先前的研究表明，重组tau在聚阴离子试剂（包括RNA）的存在下容易在体外形成寡聚体和原纤维，但所得的tau聚集体不是特别有毒的。我们发现，与TIA1共分配过程中产生的tau寡聚体比单独与RNA孵育产生的tau聚集体或与人工拥挤剂孵育产生的相分离的tau复合物的毒性更大。该途径确定了在tau相关神经退行性疾病中产生毒性tau寡聚体的潜在重要来源。我们的研究结果还揭示了一个一般原则，即相分离的RBP液滴提供了一个车辆的选择蛋白质的共配。Tau在生理条件下选择性地与TIA1共分区，强调了TIA1对Tau生物学的重要性。其他RBP，如G3BP1，能够与tau共分配，但这仅在拥挤剂存在下发生。这种类型的选择性混合可能提供了一个基础，通过无膜细胞器将功能相关的蛋白质聚集在一起，以促进特定的生物活性。
Phase separation of proteins is increasingly thought to play a fundamental role in biological processes. Recent studies show that tau protein phase separates, but the biological significance is unknown since artificial crowding agents are typically used and the resulting tau is not toxic. We now demonstrate that TIA1 potentiates RNA-mediated phase separation of tau, thereby enabling a process that occurs at physiological concentrations and also directs the formation of biologically active, highly neurotoxic oligomeric tau. Coordinated phase separation of functionally related proteins provides a general mechanism through which membraneless organelles can direct biological activities. Tau protein plays an important role in the biology of stress granules and in the stress response of neurons, but the nature of these biochemical interactions is not known. Here we show that the interaction of tau with RNA and the RNA binding protein TIA1 is sufficient to drive phase separation of tau at physiological concentrations, without the requirement for artificial crowding agents such as polyethylene glycol (PEG). We further show that phase separation of tau in the presence of RNA and TIA1 generates abundant tau oligomers. Prior studies indicate that recombinant tau readily forms oligomers and fibrils in vitro in the presence of polyanionic agents, including RNA, but the resulting tau aggregates are not particularly toxic. We discover that tau oligomers generated during copartitioning with TIA1 are significantly more toxic than tau aggregates generated by incubation with RNA alone or phase-separated tau complexes generated by incubation with artificial crowding agents. This pathway identifies a potentially important source for generation of toxic tau oligomers in tau-related neurodegenerative diseases. Our results also reveal a general principle that phase-separated RBP droplets provide a vehicle for coassortment of selected proteins. Tau selectively copartitions with TIA1 under physiological conditions, emphasizing the importance of TIA1 for tau biology. Other RBPs, such as G3BP1, are able to copartition with tau, but this happens only in the presence of crowding agents. This type of selective mixing might provide a basis through which membraneless organelles bring together functionally relevant proteins to promote particular biological activities.
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影响因子：
4.3
作者：
DeVos SL;Corjuc BT;Oakley DH;Nobuhara CK;Bannon RN;Chase A;Commins C;Gonzalez JA;Dooley PM;Frosch MP;Hyman BT
通讯作者：
Hyman BT
影响因子：
82.9
作者：
Alonso, AD;GrundkeIqbal, I;Iqbal, K
通讯作者：
Iqbal, K
影响因子：
12.7
作者：
Jiang, Lulu;Ash, Peter E. A.;Wolozin, Benjamin
通讯作者：
Wolozin, Benjamin
影响因子：
64.5
作者：
Feric M;Vaidya N;Harmon TS;Mitrea DM;Zhu L;Richardson TM;Kriwacki RW;Pappu RV;Brangwynne CP
通讯作者：
Brangwynne CP
影响因子：
5.6
作者：
Cao J;Cowan DB;Wang DZ
通讯作者：
Wang DZ