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E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions

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E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions International Journal of Molecular Sciences Review E3 Ubiquitin Ligase TRIP12: Regulation, Structure, and Physiopathological Functions 1,2, 1,2, 1,2, 1,2, , Manon Brunet y, Claire Vargas y, Dorian Larrieu y,Jérôme Torrisani * y and Marlène Dufresne 1,2,* 1 Institut National de la Santé et de la Recherche Médicale, INSERM Unit 1037, Centre de Recherches en Cancérologie de Toulouse, CEDEX 1, 31 037 Toulouse, France; [email protected] (M.B.); [email protected] (C.V.); [email protected] (D.L.) 2 Université Toulouse III-Paul Sabatier, CEDEX 9, 31 062 Toulouse, France * Correspondence: [email protected] (J.T.); [email protected] (M.D.); Tel.: +33-582-741-644 (J.T.); +33-582-741-643 (M.D.) These authors have contributed equally to this work. y Received: 25 September 2020; Accepted: 5 November 2020; Published: 12 November 2020 Abstract: The Thyroid hormone Receptor Interacting Protein 12 (TRIP12) protein belongs to the 28-member Homologous to the E6-AP C-Terminus (HECT) E3 ubiquitin ligase family. First described as an interactor of the thyroid hormone receptor, TRIP12’s biological importance was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene. Further studies showed the participation of TRIP12 in the regulation of major biological processes such as cell cycle progression, DNA damage repair, chromatin remodeling, and cell differentiation by an ubiquitination-mediated degradation of key protein substrates. Moreover, alterations of TRIP12 expression have been reported in cancers that can serve as predictive markers of therapeutic response. The TRIP12 gene is also referenced as a causative gene associated to intellectual disorders such as Clark–Baraitser syndrome and is clearly implicated in Autism Spectrum Disorder. The aim of the review is to provide an exhaustive and integrated overview of the different aspects of TRIP12 ranging from its regulation, molecular functions and physio-pathological implications. Keywords: TRIP12; E3 ubiquitin ligase; cancers; intellectual disorders 1. Introduction Thyroid hormone Receptor Interacting Protein 12 cDNA was cloned from the human myeloid KG-1 cell line and named the unidentified KIAA0045 human gene. The deduced coding sequence of KIAA0045 showed partial identity to that of the S. cerevisiae UFD4 protein (Ubiquitin Fusion Degradation 4) [1]. Another study identified Thyroid hormone Receptor Interacting Protein 12 (TRIP12) as a member of the structurally and functionally related E3 ubiquitin ligases based on the identification of a domain homologous to the E6-associated protein carboxyl terminus (HECT domain), which is a protein that induces the ubiquitin-dependent degradation of P53 in the presence of the E6 protein from the papillomavirus [2]. TRIP12 was later characterized as a thyroid hormone receptor-interacting protein by the trap yeast interaction system to isolate proteins that interact with the ligand binding/dimerization/transcriptional activation domain of the rat TR-β1 (Thyroid Receptor-β1) [3]. Fifteen cDNAs encoding Thyroid hormone Receptor Interacting Proteins (TRIPs) were isolated. All the TRIPs interacted with the Thyroid hormone Receptor (TR), but only when thyroid hormone T3 was present (TRIP1 to TRIP11) or only when T3 was absent (TRIP12 to TRIP15). Protein sequences of the fifteen TRIPs are unrelated, but sequences similarities with known proteins and functional motifs were found for nine of them Int. J. Mol. Sci. 2020, 21, 8515; doi:10.3390/ijms21228515 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 8515 2 of 34 based on blast alignment analyses with no demonstration of functional significance. The TRIP12 sequence was found to show 55% identity with the C-terminus of E6-associated protein, and more than a decade following its identification, TRIP12 was demonstrated to function as an E3 ubiquitin ligase [4]. Evidence of functional roles was later provided for the other TRIPs proteins (Supplemental Table). Among them, TRIP12 is the only TRIP family member bearing an E3 ubiquitin ligase activity. The biological importance of TRIP12 was revealed by the embryonic lethality of a murine model bearing an inactivating mutation in the TRIP12 gene [5]. Several molecular functions of TRIP12 in important cellular processes and signaling pathways have been demonstrated in recent years. Accumulating evidence indicate that TRIP12 ubiquitinates key proteins for cell homeostasis, regulates gene expression (See Section5), and plays important roles in cancers and neurological diseases. Up to now, more than 58 publications related to TRIP12 have been referenced in PubMed, half of them in the last 5 years. We have recently contributed to broadening knowledge on the role of TRIP12 by discovering a new substrate essential for pancreatic acinar cells differentiation [6] and by demonstrating that TRIP12 is a new chromatin-associated protein with several implications in the cell cycle progression and in the maintenance of genome integrity [7]. Due to its implication in several important physiological and pathological processes, TRIP12 now emerges as a protein of interest for molecular mechanisms researches and as a potential new therapeutic target. In this review, we attempt to comprehensively summarize the current knowledge from the literature and databases on TRIP12. This summary includes the gene and protein expression, the protein structure, the protein interactors and functions. We address the physio-pathological roles of TRIP12 in essential biological pathways in relation with some of its substrates. We also present the alterations of the TRIP12 gene found in neurodevelopmental disorders and cancers as well as the alterations of TRIP12 protein expression in cancers, and their consequences. Finally, we discuss the potential role of TRIP12 as a therapeutic target and highlight the need for further research studies on this protein. 2. TRIP12 mRNA and Protein Expression 2.1. TRIP12 Gene Organization In the human genome, the gene encoding for TRIP12 mRNA is located on the long arm of chromosome 2 at the locus q36.3. It spreads over nearly 168 kb (Genome Browser (see Section Software and databases)). TRIP12 mRNA expression is driven by a bidirectional promoter that also initiates the transcription of FBXO36 (F-box Only protein 36) mRNA in a head-to-head opposite direction. Bidirectional promoters are often used to control genes sharing the same regulation or encoding proteins exhibiting a similar biological process [8]. The FBXO36 gene encodes a protein that belongs to the F-box protein family. F-box is a 50 aa-domain that functions as a site for protein–protein interaction. Up to ≈ now, the functions of FBXO36 are unknown. In general, F-box proteins are part of SCF (SKP1, Cullin, F-box protein) ubiquitin ligase complexes, in which they bind to substrates for ubiquitin-mediated proteolysis [8,9]. This would be consistent with the fact that TRIP12 and FBXO36 expression are co-regulated. The 555 bp-bidirectional promoter is embedded in a 1753 bp long-CG-rich region also called CpG (Cytosine-phosphate-Guanosine) island, but the regulatory regions and methylation level of TRIP12/FBXO36 promoter remain unstudied. 2.2. TRIP12 mRNA Expression To date, 26 different TRIP12 splicing mRNA variants have been identified (www.ncbi.nlm.nih.gov) (Table1). Their length fluctuates from 9,065 (variant 4) to 10,492 nt (variant 20) with 41 to 43 exons with the exception of variants 24, 25, and 26 that contain only the first six (variants 24 and 25) or seven exons (variant 26) with a length of 5,951 (variant 26) to 6,052 nt (variant 25). Little is known regarding the expression level of the different splicing variants in human cells. It is suggested TRIP12 mRNA transcripts are a mixture of all possible isoforms, although the variant NM_001284215.1 seems to be predominant in peripheral leukocytes [10]. For the long variants, while the 50-Untranslated Region Int. J. Mol. Sci. 2019, 20, x FOR PEER REVIEW 3 of 35 Int. J. Mol. Sci. 2020, 21, 8515 3 of 34 approximately one-third of the total mRNA length (≈3700 nt), which likely indicates a regulatory function for this region (Figure 1). In fact, the existence of a short (340 nt) and a long form (3716 nt) (5 -UTR) is 180 nt-long, the 3 -Untranslated Region (3 -UTR) represents approximately one-third 0 of TRIP12≈ 3′-UTR mRNA was0 reported [11]. The different0 sites of transcriptional termination are of the total mRNA length ( 3700 nt), which likely indicates a regulatory function for this region explained by the presence≈ of two consensus polyadenylation signals (Figure 1). These two variants (Figuredisplay1). In different fact, the translation existence efficiency of a short in (340 response nt) and to an a longactivation form of (3716 the mTORC nt) of TRIP12(mammalian30-UTR Target mRNA was reportedOf Rapamycin [11]. Complex The different 1) signaling sites of pathway transcriptional where the terminationshort form is more are explained efficiently bytranslated the presence [11]. of two consensusWith reference polyadenylation to the Human Protein signals Atlas (Figure (see1 ).Se Thesection Software two variants and databases), display ditheff expressionerent translation of efficiencyTRIP12 in mRNA response is ubiquitous to an activation in human of the tissues mTORC even (mammalianif levels of mRNA Target vary Of between Rapamycin tissues. Complex For 1) signalingexample, pathway TRIP12 where mRNA the shortis highly form expressed is more e ffiinciently testis and translated in muscles [11].
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