Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination
Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination
复制标题
DOI：
10.1128/mcb.00643-14
复制
发表时间：
2014-12-01
影响因子：
5.3
通讯作者：
Gueydan, Cyril
中科院分区：
文献类型：
--
作者：
Long Vo Ngoc;Wauquier, Corinne;Gueydan, Cyril
TIS 11/tristetraprolin（TTP）CCCH串联锌指蛋白是使在其3'非翻译区中携带富含AU元件（ARE）的mRNA不稳定的主要效应物。在这份报告中，我们证明了果蝇dTIS 11蛋白是短暂的，由于其快速的泛素不依赖性降解的蛋白酶体。我们的数据表明，这种机制是紧密相关的内在非结构化，无序的N-和C-末端结构域的蛋白质。此外，我们表明，TTP，哺乳动物TIS 11/TTP蛋白原型，具有相同的三维特征，并通过相同的蛋白水解途径降解dTIS 11，从而表明这种机制在整个进化过程中是保守的。最后，我们观察到磷酸化依赖性抑制dTIS 11和TTP降解的蛋白酶体在体外，提高了这种修饰直接影响这些蛋白质的蛋白酶体识别的可能性。作为一个群体，RNA结合蛋白（RNA-BPs）被描述为富含内在无序区域，从而提高了我们发现的TIS 11/TTP周转机制在其他RNA-BPs中广泛存在的可能性。
The TIS11/tristetraprolin (TTP) CCCH tandem zinc finger proteins are major effectors in the destabilization of mRNAs bearing AU-rich elements (ARE) in their 3' untranslated regions. In this report, we demonstrate that the Drosophila melanogaster dTIS11 protein is short-lived due to its rapid ubiquitin-independent degradation by the proteasome. Our data indicate that this mechanism is tightly associated with the intrinsically unstructured, disordered N- and C-terminal domains of the protein. Furthermore, we show that TTP, the mammalian TIS11/TTP protein prototype, shares the same three-dimensional characteristics and is degraded by the same proteolytic pathway as dTIS11, thereby indicating that this mechanism has been conserved across evolution. Finally, we observed a phosphorylation-dependent inhibition of dTIS11 and TTP degradation by the proteasome in vitro, raising the possibility that such modifications directly affect proteasomal recognition for these proteins. As a group, RNA-binding proteins (RNA-BPs) have been described as enriched in intrinsically disordered regions, thus raising the possibility that the mechanism that we uncovered for TIS11/TTP turnover is widespread among other RNA-BPs.