cells Review To Ubiquitinate or Not to Ubiquitinate: TRIM17 in Cell Life and Death Meenakshi Basu-Shrivastava † , Alina Kozoriz † , Solange Desagher and Iréna Lassot * Institut de Génétique Moléculaire de Montpellier, University Montpellier, CNRS, Montpellier, France; [email protected] (M.B.-S.); [email protected] (A.K.); [email protected] (S.D.) * Correspondence: [email protected] † These authors contribute equally to this review. Abstract: TRIM17 is a member of the TRIM family, a large class of RING-containing E3 ubiquitin- ligases. It is expressed at low levels in adult tissues, except in testis and in some brain regions. However, it can be highly induced in stress conditions which makes it a putative stress sensor required for the triggering of key cellular responses. As most TRIM members, TRIM17 can act as an E3 ubiquitin-ligase and promote the degradation by the proteasome of substrates such as the antiapoptotic protein MCL1. Intriguingly, TRIM17 can also prevent the ubiquitination of other proteins and stabilize them, by binding to other TRIM proteins and inhibiting their E3 ubiquitin-ligase activity. This duality of action confers several pivotal roles to TRIM17 in crucial cellular processes such as apoptosis, autophagy or cell division, but also in pathological conditions as diverse as Parkinson’s disease or cancer. Here, in addition to recent data that endorse this duality, we review what is currently known from public databases and the literature about TRIM17 gene regulation and expression, TRIM17 protein structure and interactions, as well as its involvement in cell physiology and human disorders. Citation: Basu-Shrivastava, M.; Kozoriz, A.; Desagher, S.; Lassot, I. To Keywords: TRIM17; ubiquitination; proteolysis; apoptosis; autophagy; mitosis; Parkinson’s disease; Ubiquitinate or Not to Ubiquitinate: autism; cancer TRIM17 in Cell Life and Death. Cells 2021, 10, 1235. https://doi.org/ 10.3390/cells10051235 1. Introduction Academic Editor: Manabu Kurokawa The tripartite motif (TRIM) family represents the largest subfamily of RING-containing E3 ubiquitin-ligases [1]. In humans, it includes more than 80 members [2–4]. TRIM proteins Received: 26 April 2021 are characterized by the presence of a highly conserved tripartite motif at the N-terminus Accepted: 13 May 2021 that is composed of a RING domain, one or two B-boxes (B1 and B2) and a coiled-coil (CC) Published: 18 May 2021 domain. It is followed by a highly variable carboxy-terminal domain, which categorizes the different TRIMs into 12 distinct subgroups (C-I to C-XII) [1] (Figure1). The subgroup Publisher’s Note: MDPI stays neutral C-IV is characterized by a PRY-SPRY domain that represents the most common C-terminal with regard to jurisdictional claims in domain, accounting for about half of all known TRIMs [2,5,6]. The RING domain confers published maps and institutional affil- iations. to TRIM proteins their E3 ligase activity [7], the other conserved domains being mostly involved in protein–protein interactions. The specific combination and order of the different domains within the tripartite motif, but also the spacing between each domain, is highly conserved. This suggests that the tripartite motif has been selectively maintained to perform specialized functions, such as ubiquitination, and represents a functional structure Copyright: © 2021 by the authors. rather than a set of separate modules [1,8]. Licensee MDPI, Basel, Switzerland. Ubiquitination involves the sequential action of an E1 ubiquitin-activating enzyme, This article is an open access article an E2 ubiquitin-conjugating enzyme and an E3 ubiquitin protein ligase which specifically distributed under the terms and conditions of the Creative Commons recognizes the substrate, binds an E2 enzyme and facilitates the covalent binding of Attribution (CC BY) license (https:// ubiquitin (a 76-residue polypeptide highly conserved throughout evolution) mainly to a creativecommons.org/licenses/by/ specific Lys residue of the substrate protein [9]. Ubiquitin itself can be ubiquitinated on 4.0/). different residues (K6, K11, K27, K29, K33, K48 and K63 or the N-terminal methionine Cells 2021, 10, 1235. https://doi.org/10.3390/cells10051235 https://www.mdpi.com/journal/cells Cells 2021, 10, x FOR PEER REVIEW 2 of 28 Cells 2021, 10, 1235 2 of 28 different residues (K6, K11, K27, K29, K33, K48 and K63 or the N-terminal methionine residue) to form ubiquitin chains with many different conformations. Depending on the number of the substrate Lys residues that are modified, the number of ubiquitin molecules thatresidue) are conjugated to form ubiquitin and the chainsconformation with many of the different chains formed, conformations. this cascade Depending of reactions on resultsthe number in mono-, of the multi- substrate or poly-ubiquitination Lys residues that that are determine modified, thethe fate number of the of substrates ubiquitin [10].molecules For example, that are K48-polyubiquitinated conjugated and the conformation substrates are of thegenerally chains degraded formed, thisby the cascade pro- teasomeof reactions [11], results while in K63-polyubiquitinated mono-, multi- or poly-ubiquitination or monoubiquitinated that determine substrates the are fate rather of the eliminatedsubstrates [by10 ].autophagy For example, [12]. K48-polyubiquitinated TRIM proteins, therefore, substrates contribute are generally to the efficient degraded re- movalby the of proteasome short-lived [ 11or], misfolded while K63-polyubiquitinated proteins and protein aggregates, or monoubiquitinated mainly by the substrates ubiqui- are rather eliminated by autophagy [12]. TRIM proteins, therefore, contribute to the tin–proteasome system (UPS) but also by autophagy, and may participate in the crosstalk efficient removal of short-lived or misfolded proteins and protein aggregates, mainly by between these two systems [13]. the ubiquitin–proteasome system (UPS) but also by autophagy, and may participate in the TRIM17 (Tripartite motif-containing 17) also known as RNF16 (Ring Finger protein crosstalk between these two systems [13]. 16) or terf (testis RING finger protein) is part of the Class C-IV subfamily of TRIMs [1] TRIM17 (Tripartite motif-containing 17) also known as RNF16 (Ring Finger protein 16) or (Figure 1). As such, TRIM17 contains a PRY-SPRY domain at its C-terminal extremity. terf (testis RING finger protein) is part of the Class C-IV subfamily of TRIMs [1](Figure1 ). TRIM17 was initially isolated from rat and human testis cDNA libraries in 1998 [14]. Both As such, TRIM17 contains a PRY-SPRY domain at its C-terminal extremity. TRIM17 was cDNAs encode a 477 amino acids protein that has been subsequently found to be ex- initially isolated from rat and human testis cDNA libraries in 1998 [14]. Both cDNAs pressed at low levels in various tissues [15]. This weak expression, which makes it difficult encode a 477 amino acids protein that has been subsequently found to be expressed at to detect with antibodies, may explain why TRIM17 was not studied for a long time. The low levels in various tissues [15]. This weak expression, which makes it difficult to detect E3with ubiquitin-ligase antibodies, may activity explain of TRIM17 why TRIM17 was first was demonstrated not studied forin 2009 a long [15] time. and Theits first E3 cellularubiquitin-ligase function activitywas described of TRIM17 in 2010, was firstwhen demonstrated we showed that in 2009 mouse [15] Trim17 and its firstis both cellular nec- essaryfunction and was sufficient described for in neuronal 2010, when apoptosis we showed [16]. Subsequently, that mouse Trim17 we and is both others necessary have iden- and tifiedsufficient different for neuronal substrates apoptosis and partners [16]. Subsequently, of TRIM17 weand and provided others have evidence identified that differentTRIM17 playssubstrates an important and partners role of in TRIM17 key cellular and provided processes. evidence Although that it TRIM17 is low in plays most an situations, important TRIM17role in key expression cellular processes. can be dramatically Although itinduced is low in following most situations, different TRIM17 cellular expression stresses, giv- can ingbe dramaticallyit the role of induced a sentinel following ready to different trigger cellularthe appropriate stresses, givingcellular it theresponse role of [15,17,18]. a sentinel Here,ready we to triggerreview thethe appropriatecurrent knowledge cellular on response TRIM17 [15 gene,17,18 regulation,]. Here, we substrates review the and current part- nersknowledge of the TRIM17 on TRIM17 protein,gene regulation,its cellular significance substrates and and partners the emerging of the TRIM17 role of TRIM17 protein, itsin severalcellular human significance diseases. and the emerging role of TRIM17 in several human diseases. Figure 1. Classification of the TRIM proteins family. In bold, TRIM17 and its known TRIM partners described in this review. Figure 1. Classification of the TRIM proteins family. In bold, TRIM17 and its known TRIM partners described in this Adapted from [19,20]. review. Adapted from [19,20]. Cells 2021, 10, x FOR PEER REVIEW 3 of 28 2. Structure and Regulation of the TRIM17 Gene 2.1. Structure of the TRIM17 Gene Many TRIM genes exhibit the same genomic organization, with 6-7 exons spanning a 10 kb region [8]. The human TRIM17 gene is located on 1q42.13 and spans less than 10 kb of the genome (University of California Santa Cruz (UCSC) Genome browser, genome build GRCh38/hg38, December 2013). In both humans and rodents, the gene is composed of 7 coding exons. In humans, its transcription seems to be driven by a single promoter and an alternatively spliced exon is present downstream the sixth coding exon (Figure 2). This could explain the existence of several TRIM17 transcript isoforms that involve not only the 3′ of the gene and several polyadenylation signals but also the coding region. Cells 2021, 10, 1235 3 of 28 In both humans and rodents, TRIM17 is located close to TRIM11 (Figure 2). It is note- worthy that TRIM11 also belongs to the subgroup C-IV of TRIM proteins and is the closest paralog gene of TRIM17 [21] (data from ensembl.org, v.103 21 February 2021), with 46% 2.