Rapid Proteasomal Degradation of Posttranscriptional Regulators of the TIS11/Tristetraprolin Family Is Induced by an Intrinsically Unstructured Region Independently of Ubiquitination |
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| Authors: | Long Vo Ngoc Corinne Wauquier Romuald Soin Sabrina Bousbata Laure Twyffels Véronique Kruys Cyril Gueydan |
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| Affiliation: | aLaboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium;bLaboratoire de Microbiologie et Biologie Structurale, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium;cCenter for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Gosselies, Belgium |
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| Abstract: | 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. |
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