title: Rapid proteasomal degradation of posttranscriptional regulators of the TIS11/tristetraprolin family is induced by an intrinsically unstructured region independently of ubiquitination.
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.
authors.affiliation: Laboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Long Vo
authors.initials: LV
authors.lastname: Ngoc
authors.affiliation: Laboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Corinne
authors.initials: C
authors.lastname: Wauquier
authors.affiliation: Laboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Romuald
authors.initials: R
authors.lastname: Soin
authors.affiliation: Laboratoire de Microbiologie et Biologie Structurale, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Bousbata
authors.affiliation: Laboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Laure
authors.initials: L
authors.lastname: Twyffels
authors.affiliation: Laboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium Center for Microscopy and Molecular Imaging, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: Véronique
authors.initials: V
authors.lastname: Kruys
authors.affiliation: Laboratoire de Biologie Moléculaire du Gène, IBMM, Faculté des Sciences, Université Libre de Bruxelles, Gosselies, Belgium cgueydan@ulb.ac.be.
authors.forename: Cyril
authors.identifier: http://orcid.org/0000-0003-3097-7667
authors.initials: C
authors.lastname: Gueydan
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D063307:AU Rich Elements; D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000378:metabolism*; D051379:Mice; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D020871:RNA Stability / Q000235:genetics; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051816:Tristetraprolin / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D020413:3' Untranslated Regions; D029721:Drosophila Proteins; D064267:Intrinsically Disordered Proteins; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; C572932:Tis11 protein, Drosophila; D051816:Tristetraprolin; D046988:Proteasome Endopeptidase Complex