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Abstract：
Tubby-like proteins (TULPs) are characterized by a conserved C-terminal domain that binds phosphoinositides. Collectively, mammalian TULP1-4 proteins play essential roles in intracellular transport, cell differentiation, signaling, and motility. Yet, little is known about how the function of these proteins is regulated in cells. Here, we present the protein-protein interaction network of TULP3, a protein that is responsible for the trafficking of G-protein-coupled receptors to cilia and whose aberrant expression is associated with severe developmental disorders and polycystic kidney disease. We identify several protein interaction nodes linked to TULP3 that include enzymes involved in acetylation and ubiquitination. We show that acetylation of two key lysine residues on TULP3 by p300 increases TULP3 protein abundance and that deacetylation of these sites by HDAC1 decreases protein levels. Furthermore, we show that one of these sites is ubiquitinated in the absence of acetylation and that acetylation inversely correlates with ubiquitination of TULP3. This mechanism is evidently conserved across species and is active in zebrafish during development. Finally, we identify this same regulatory module in TULP1, TULP2, and TULP4 and demonstrate that the stability of these proteins is similarly modulated by an acetylation switch. This study unveils a signaling pathway that links nuclear enzymes to ciliary membrane receptors via TULP3, describes a dynamic mechanism for the regulation of all tubby-like proteins, and explores how to exploit it pharmacologically using drugs.
摘要：
管状样蛋白(TULPs)的特征在于与磷酸肌醇结合的保守的C-末端结构域。总的来说，哺乳动物的TULP1-4蛋白在细胞内运输中发挥重要作用，细胞分化，信令,和运动性。然而，人们对这些蛋白质的功能在细胞中是如何调节的知之甚少。这里,我们介绍了TULP3的蛋白-蛋白相互作用网络,该蛋白负责将G蛋白偶联受体转运至纤毛,其异常表达与严重的发育障碍和多囊肾疾病有关.我们确定了与TULP3连接的几个蛋白质相互作用节点，包括参与乙酰化和泛素化的酶。我们表明，通过p300对TULP3上的两个关键赖氨酸残基进行乙酰化会增加TULP3蛋白质的丰度，而HDAC1对这些位点的去乙酰化会降低蛋白质水平。此外，我们表明，在没有乙酰化的情况下，这些位点之一被泛素化，并且乙酰化与TULP3的泛素化成反比。这种机制显然在物种之间是保守的，并且在斑马鱼的发育过程中具有活性。最后,我们在TULP1,TULP2和TULP4中鉴定了相同的调节模块,并证明这些蛋白的稳定性同样受到乙酰化开关的调节.这项研究揭示了通过TULP3将核酶与睫状膜受体连接的信号通路，描述了调节所有管状蛋白的动态机制，并探索如何利用它的药理学使用药物。
