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TRIM32: a Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis

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TRIM32: a Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis biomolecules Review TRIM32: A Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis Simranjot Bawa 1, Rosanna Piccirillo 2 and Erika R. Geisbrecht 1,* 1 Department of Biochemistry and Molecular Biophysics, Kansas State University, Manhattan, KS 66506, USA; [email protected] 2 Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156 Milan, Italy; [email protected] * Correspondence: [email protected]; Tel.: +1-(785)-532-3105 Abstract: Human tripartite motif family of proteins 32 (TRIM32) is a ubiquitous multifunctional protein that has demonstrated roles in differentiation, muscle physiology and regeneration, and tumor suppression. Mutations in TRIM32 result in two clinically diverse diseases. A mutation in the B-box domain gives rise to Bardet–Biedl syndrome (BBS), a disease whose clinical presentation shares no muscle pathology, while mutations in the NHL (NCL-1, HT2A, LIN-41) repeats of TRIM32 causes limb-girdle muscular dystrophy type 2H (LGMD2H). TRIM32 also functions as a tumor suppressor, but paradoxically is overexpressed in certain types of cancer. Recent evidence supports a role for TRIM32 in glycolytic-mediated cell growth, thus providing a possible mechanism for TRIM32 in the accumulation of cellular biomass during regeneration and tumorigenesis, including in vitro and in vivo approaches, to understand the broad spectrum of TRIM32 functions. A special emphasis is placed on the utility of the Drosophila model, a unique system to study glycolysis and anabolic pathways that contribute to the growth and homeostasis of both normal and tumor tissues. Citation: Bawa, S.; Piccirillo, R.; Geisbrecht, E.R. TRIM32: A Keywords: muscle; costamere; muscular dystrophy; cancer Multifunctional Protein Involved in Muscle Homeostasis, Glucose Metabolism, and Tumorigenesis. Biomolecules 2021, 11, 408. https:// 1. The TRIM Family of Proteins doi.org/10.3390/biom11030408 The tripartite motif family of proteins (TRIM) is characterized by the presence of an N- terminal RING (really interesting new gene) finger followed by one or two B-box domains Academic Editor: Paolo Cascio (BB1 and BB2) and a coiled-coil region with a variable C-terminus (Figure1A) [ 1,2]. The TRIM family consists of approximately 70 protein members involved in a plethora of biolog- Received: 8 February 2021 ical processes, including apoptosis, cell cycle regulation, muscle homeostasis, and the innate Accepted: 6 March 2021 Published: 10 March 2021 immune response [3,4]. Each domain has independent functions, and the variability in the C-terminal region defines the structural and biochemical properties of the protein and im- Publisher’s Note: MDPI stays neutral parts target specificity. The TRIM family of proteins is sorted into nine categories classified with regard to jurisdictional claims in as C-I through C-XI based upon the composition of the C-terminal domain (Figure1B) [2]. published maps and institutional affil- The C-VII subclass includes proteins with five or six NHL (NCL-1, HT2A, LIN-41) repeats, iations. which are thought to primarily mediate protein–protein interactions. TRIM-NHL proteins also bind RNAs and are key regulators of cell growth, proliferation, and differentiation [5]. There are four TRIM-NHL proteins encoded in Drosophila melanogaster, Mus musculus, and Homo sapiens followed by five in Caenorhabditis elegans [5] (Figure1C). One of these TRIM-NHL proteins, TRIM32, was uncovered as a protein that binds to Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. HIV-1 Tat, a key transactivator of viral transcription [6]. Since this initial discovery, the This article is an open access article biological roles of TRIM32 have rapidly expanded [2,3,7–9]. Human TRIM32 is expressed distributed under the terms and in a variety of tissues, including skeletal muscle, with elevated levels eminent in the brain conditions of the Creative Commons and heart [10]. The Drosophila ortholog of TRIM32 is enriched in larval and adult muscle Attribution (CC BY) license (https:// tissue and demonstrates structural and functional conservation across species [11–13]. This creativecommons.org/licenses/by/ review highlights classical and emerging roles of TRIM32 as a multifunctional protein 4.0/). in a multitude of developmental and physiological functions, as well as summarizes its Biomolecules 2021, 11, 408. https://doi.org/10.3390/biom11030408 https://www.mdpi.com/journal/biomolecules Biomolecules 2021, 11, x FOR PEER REVIEW 2 of 25 Biomolecules 2021, 11, 408 This review highlights classical and emerging roles of TRIM32 as a multifunctional2 of pro- 23 tein in a multitude of developmental and physiological functions, as well as summarizes involvementits involvement in regulatingin regulating glycolytic glycolytic enzymes enzymes to promoteto promote growth growth in in both both normal normal and and cancerouscancerous tissues.tissues. Figure 1. ClassificationClassification ofof thethe tripartitetripartite motifmotiffamily family of of proteins proteins 32 32 (TRIM). (TRIM) (.A (A) General) General schematic schematic of of a TRIMa TRIM protein. protein. The The NN-terminus-terminus is comprised ofof aa reallyreally interestinginteresting newnew gene gene (RING) (RING) domain, domain, one one or or two two B-box B-box regions, regions, and and a coiled-coila coiled-coil domain followedfollowed byby a a variable variable C-terminus. C-terminus. (B )( TableB) Table representing representing different different categories categories of TRIM of TRIM proteins. proteins. (C) Different (C) Different NHL NHL(NCL-1, (NCL HT2A,-1, HT2A, LIN-41) LIN proteins-41) proteins encoded encoded in vertebrates in vertebrates and invertebrates and invertebrates (adapted (adapted from WILLIAMS from WILLIAMS et al. 2019). et al. 2019). 1.1.1.1. Structural andand FunctionalFunctional OrganizationOrganization of of TRIM32 TRIM32 MammalianMammalian TRIM32TRIM32 isis a part of the largest subfamily of RING E3 E3 ligases ligases involved involved in inregulating regulating multifaceted multifaceted post post-translational-translational modifica modificationstions of cellular of cellular proteins proteins through through ubiq- ubiquitinationuitination [2,7]. [ 2The,7]. N The-terminus N-terminus consists consists of the oftypical the typical TRIM TRIMmotifs, motifs, including including the catalytic the catalyticRING domain, RING domain, a single aB single-box domain B-box domain (Type II), (Type and II), a andcoiled a coiled-coil-coil region, region, followed followed by six byC-terminal six C-terminal NHL repeats NHL repeats (Figure (Figure 2A). Conserved2A). Conserved cysteine cysteine and histidine and histidine residues residues spaced spacedout in the out core in the of the core RING of the domain RING domaincoordinate coordinate two zinc two ions zinc in a ions cross in-bridge a cross-bridge fashion to fashionprovide to structural provide structuralmaintenance maintenance and to ensure and tobiological ensure biological activity [14,15]. activity For [14 ,a15 protein]. For a to proteinexhibit toE3 exhibit ligase activity E3 ligase, the activity, RING the domain RING domainmust possess must possessa proline a prolineresidue residue after cysteine after cysteine at the seventh position; this residue is missing in nematode LIN-41 and the protein Biomolecules 2021, 11, x FOR PEER REVIEW 3 of 25 at the seventh position; this residue is missing in nematode LIN-41 and the protein lacks catalytic activity [16,17]. The crystal structure of the TRIM32 RING domain reveals a di- mer of four alpha helices where both the N- and C-termini are located near the proximity of the core [18]. This dimerization promotes the association of E2-Ubiquitin conjugates and enhances the transfer of ubiquitin moieties. Another zinc-binding region is the B-box domain type II and, similar to the RING domain, this domain coordinates two zinc ions in a similar cross-brace manner. Typically, the B-box domain type II presents a two-turn α-helix followed by two short β-strands separated by a type-2 β-turn with two structured Biomolecules 2021, 11, 408 loops adjacent to the helix [19]. The B-box domains, together with the antiparallel coiled3 of 23 - coil region, allow for the formation of higher order complexes, but the domain itself is not crucial for catalytic activity. Instead, this region has been shown to influence the rate of ubiquitinlacks catalytic chain activity assembly [16 ,and17]. contribute The crystal to structure the subcellular of the TRIM32 localization RING of domain TRIM32 reveals [20]. a dimerEach of fourNHL alpha repeat helices is comprised where both of theshort N- stretches and C-termini of about are located40 amino near acids. the proximityThe X-ray structureof the core of [the18]. TRIM32 This dimerization NHL motif promotes reveals a the β propeller association whe ofre E2-Ubiquitin each NHL repeat conjugates folds intoand four enhances antiparallel the transfer β sheets of ubiquitinarranged moieties.toroidally Another around zinc-bindinga central axis region (Figure is 2B) the [12,21]. B-box Thesedomain NHL type repeats II and, are similar essential to the for RING mediating domain, protein this domain–protein coordinates interactions two and zinc likely ions inpro- a videsimilar substrate cross-brace specificity manner. [2]. Typically, It has the reported B-box domain that the type TRIM32 II presents RING a two-turn domainα-helix inde- pendentlyfollowed bymediates two short dimerizationβ-strands separatedand
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