TRIM-NHL proteins in development and disease

Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

Contents lists available at ScienceDirect

Seminars in Cell & Developmental Biology journal homepage: www.elsevier.com/locate/semcdb

TRIM-NHL proteins in development and disease Cristina Tocchini, Rafal Ciosk ∗ Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland

a r t i c l e

i n f o

Article history: Available online 26 October 2015 Keywords: TRIM NHL Brat Mei-P26 TRIM32 LIN-41 TRIM71 Bardet-Biedl syndrome Limb girdle muscular dystrophy 2H Sarcotubular myopathy

a b s t r a c t TRIM-NHL proteins are key regulators of developmental transitions, for example promoting differentiation, while inhibiting cell growth and proliferation, in stem and progenitor cells. Abnormalities in these proteins have been also associated with human diseases, particularly affecting muscular and neuronal functions, making them potential targets for therapeutic intervention. The purpose of this review is to provide a systematic and comprehensive summary on the most studied TRIM-NHL proteins, highlighting examples where connections were established between structural features, molecular functions and biological outcomes. © 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

1. The TRIM-NHL proteins: domains and associated molecular functions The TRIpartite Motif (TRIM) is constituted by three main domains: a Really Interesting New Gene (RING) finger, one or, more commonly, two B-Box-type zinc fingers (BB1 and BB2) and a Coiled-Coil (CC) (Fig. 1A). The TRIM is always located towards the N-terminus of the protein and the order of, as well as the spacing between individual domains, is highly conserved [1]. TRIM-NHL proteins (referred to as “C-VII” subfamily) represent one of the nine subfamilies of TRIM proteins (from “C-I” to “C-IX”), whose classification is based on the presence of an additional domain, NHL, which is positioned C-terminally from the TRIM [2]. The NHL stands for NCL-1/HT2A/LIN-41, the proteins in which the domain was initially described. A filamin (immunoglobulin) domain is often found immediately before the NHL domain [3] (Fig. 1A). Thus, the TRIM-NHL proteins consist of several distinct domains, potentially endowing them with functional flexibility. The RING domain is defined by a regular series of cysteine (Cys C) and histidine (His - H) residues, which coordinate two zinc ions in a “cross-brace” fashion, where Cys in positions 1, 2, 5, 6 bind the first zinc ion and Cys and Hys residues in position 3, 4, 7, 8 bind the second one (Fig. 1B; [4–6]). Conserved Cys and His residues are located in the core of the domain and their binding to the zinc ions is

∗ Corresponding author. Tel.: +41 61 697 5203; fax: +41 61 697 3976. E-mail address: [email protected] (R. Ciosk).

essential for maintaining the domain structure [4,5]. The RING domain can act as an E3 ubiquitin ligase (Fig. 1C). On one hand, it directly interacts with an E2 conjugating enzyme, which receives the ubiquitin peptide from an E1 ubiquitin-activating enzyme. On the other hand, it associates with a protein substrate, bringing it to the proximity of E2. Notably, not all RING domains can act as E3 ubiquitin ligases. To possess E3 activity, a RING domain must include a proline immediately after the Cys residue in position 7 [7] and this residue is missing in nematode LIN-41 proteins [8]. Furthermore, untypical TRIM proteins – Brat and Wech – lack the RING domain, suggesting that the other domains can function independently of the RING domain. The B-Boxes (BBs) are also zinc-binding motives that come in two flavors (type I and type II), presenting similar, although distinct, consensus sequences (Fig. 1B; [1,5,9]). The BBs resemble the RING, ZZ and U-box domains of E3 and E4 ubiquitin ligases, suggesting that the BBs may, in principle, either act as E3s per se or enhance the E3 RING domain activity [10]. Similarly to the RING domain, BBs also coordinate their two zinc ions in a “cross-brace” fashion [9–11]. Although the precise function of BBs remains to be demonstrated, they have been proposed, together with the CC domain, to provide the binding site for a substrate ubiquitinated via the RING domain [10]. The coiled-coil domain consists of roughly hundred amino acids, whose amino acid sequence is not conserved. Despite that, the secondary structure is usually partitioned into two or three coiled-coil motives, mainly constituted by ␣-helices that form a “rope-like” structure, stabilized by hydrophobic interactions, often mediated

http://dx.doi.org/10.1016/j.semcdb.2015.10.017 1084-9521/© 2015 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

53

Fig. 1. Functional domains of TRIM-NHL proteins. (A) Architecture of a typical TRIM-NHL protein. Composition of the TRIM (RING, BB1/2 and CC) and the immunoglobulin-NHL (Filamin and NHL) portions of the protein. The domains are aligned from the N- (left) to the C-terminus (right) as they normally occur in TRIM-NHL proteins. (B) Consensus zinc finger motives present in the TRIM domain. The types of motives are in bold, key residues of the sequences are in red: RING, BB1 and BB2. “C” stands for cysteine, “H” for histidine, “D” for aspartic acid and “X” for any amino acid. Numbers in brackets represent the range of a certain residue. (C) List of described molecular functions for specific domains of TRIM-NHL proteins. Specific substrates and/or associated proteins and RNAs are indicated. (For interpretation of the color information in this figure legend, the reader is referred to the web version of the article.)

by leucines [10,12]. The CC domain allows the formation of homoor heterodimers, promotes the formation of protein complexes (e.g., recruiting the substrate for ubiquitination) and can help to define certain subcellular compartments [1]. The precise function of this domain in TRIM-NHL proteins awaits clarification, but the domain has been implicated in mRNA regulation (Fig. 1C; [13]). The filamin domain is often associated with the NHL repeats at the C-termini of TRIM-NHL proteins [3], potentially indicating a shared molecular function. The filamin domain exhibits a classic immunoglobulin-like structure, constituted by seven ␤-strands arranged in two antiparallel ␤-sheets [8,14], whose function, in the context of TRIM-NHL proteins, has been recently linked to mRNA regulation. Specifically, the filamin domain, together with the CC, was proposed to recruit proteins regulating mRNA translation [13]. The NHL domain consists of five or six repeats, of roughly forty residues each, and folds into a barrel-like ␤-propeller structure. The NHL repeats have been generally regarded as structural units involved in protein binding [15,16]. However, in TRIM-NHL proteins, one of the two propeller surfaces is highly positively charged and has been proposed to directly associate with the negatively

charged RNA phosphate backbone (Fig. 1C; [17–19]). How the specificity of RNA binding is achieved remains an important problem for the future research. Below, we discuss biological functions of most-studied TRIM-NHL family members, highlighting examples where their mutations have been linked to human diseases (Table 1). 2. Most studied family members: biological roles and associated human diseases 2.1. Brat, Mei-P26, NCL-1 and NHL-2 Several TRIM-NHL family members have been examined in model organisms (Fig. 2). The Drosophila melanogaster Brat is perhaps the most studied family member. The name brat, BRAin Tumor, comes from the larval brat phenotype [20]. In normal development, Brat controls the decision between differentiation and self-renewal in larval neuroblast lineages, which give rise to adult neurons. During asymmetric division of a neuroblast Brat, together with the transcription factor (TF) Prospero, segregates into one

54

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

Table 1 Described disease for altered TRIM-NHL protein function. Protein

Aberration type

Affected domain

Disease

Reference

TRIM2

Point mutation (E227V) Higher protein levels

CC* All

Axonal neuropathy AD

Ylikallio et al. [43] Schonrock et al. [42]

TRIM3

Complete deletion Higher protein levels

All All

Glioma (25%) Schizophrenia

Boulay et al. [48] Martins-de-Souza et al. [53]

TRIM71

Higher protein levels Higher protein levels

All All

hepatocellular carcinoma myxoid liposarcoma

Chen et al. [47] De Cecco et al. [101]

TRIM32

Point mutation (P130S) Point mutation (H452T) Point mutation (D487N) Point mutation (D487N) Point mutation (R394H) Frameshift mutation (T520TfsX13) Small deletion (D588del) Frameshift mutation (I590LfsX38) Non-sense mutation (R136Stop) Complete deletion Higher protein levels Higher protein levels Higher protein levels

BB1 NHL NHL NHL NHL NHL NHL NHL From BB1 All All All All

BBS type 11 Schizophrenia STM LGMD2H LGMD2H LGMD2H LGMD2H LGMD2H LGMD2H Non-specific LGMD2H AD Stress-induced affective behaviors Head and neck squamous cell carcinomas

Chiang et al., 2006 Farous et al., 2004 Schoser et al., 2005 Frosk et al., 2002; Frosk et al. 2005 Saccone et al., 2008 Saccone et al., 2008 Saccone et al., 2008 Coss et al., 2009 Neri et al., 2013 Nectoux et al. [66] Yokota et al. [69] Ruan et al. [70] Horn et al. [73]

List of human diseases that were linked to alterations of TRIM-NHL proteins – substitutions in the domains and/or altered protein expression. * Protein levels are reduced. AD: Alzheimer Disease; STM: SarcoTubular Myopathy; LGMD2H: Limb Girdle Muscular Dystrophy type 2H.

Fig. 2. Phylogenetic tree of TRIM-NHL proteins. Phylogenetic tree showing the most studied TRIM-NHL proteins (with species indicated in brackets). Alignment of fulllength protein sequences was made with Clustal Omega (http://www.ebi.ac.uk/ Tools/msa/clustalo/). The results were sent to ClustalW2 Phylogeny (http://www. ebi.ac.uk/Tools/phylogeny/clustalw2 phylogeny/) and a neighbor-joining clustering method with distance correction off was used to obtain the phylogenetic tree.

daughter cell (the so-called intermediate progenitor cell) permitting its differentiation, whereas the other cell, lacking Brat and Prospero, continues self-renewing [21]. Brat is an atypical TRIMNHL protein as it lacks the RING domain. Instead, it is the NHL domain that is critical for preventing tumor formation, as different point mutations in the NHL repeats phenocopy the null allele [20]. The initial insight into the biological role of Brat came from the work on its Caenorhabditis elegans counterpart, NCL-1. While the loss of NCL-1 resulted in an increased size of nucleoli and higher levels of rRNA, these phenotypes were rescued by the ectopic expression of Brat [22,23]. Consequently, the authors speculated that the tumor

phenotype in D. melanogaster was caused by an increased synthesis of ribosomal RNA and unchecked cell growth [22]. This scenario was supported by the subsequent observation that many genes involved in metabolism, cell cycle, transcriptional control and ribosomal synthesis, were overexpressed in brat mutants [24]. In addition to its role in brain development, Brat has been shown to function in other developmental contexts. It acts as a differentiation factor and inhibitor of cell renewal in differentiating cytoblasts (cells derived from ovarian germline stem cells (GSCs)) [25]. Brat also regulates neuromuscular synaptic growth in neuromuscular junction synapses [26]. In both cases, Brat has been shown to act through the NHL repeats, repressing translation of mad, which encodes an effector of the BMP (Bone Morphogenetic Protein) signaling pathway. Moreover, the NHL domain of Brat is required in early embryos to repress translation of the hunchback mRNA. This repression also involves the RNA binding proteins (RBPs) Nanos and Pumilio [27]. Although the RNA binding of Brat was suggested to depend on Pumilio [17], recent work demonstrated that Brat NHL repeats directly associate with RNA through the electropositive surface of the domain [18]. Very recently, the RNA binding motif of Brat has been uncovered [28], which is a big step toward understanding the molecular role of Brat in mRNA regulation. Finally, in addition to the above functions of Brat mediated by the NHL domain, recent findings suggest that the BBs also play a critical role in cell fate specification. Specifically, the BBs have been shown to be involved in the specification of the intermediate progenitor cells, independently from the role in asymmetric protein segregation. Although the exact underlying mechanism remains unclear, the BBs seem to be indirectly responsible for the repression of the ␤-catenin/Armadillo activity [29]. Another well-studied D. melanogaster TRIM-NHL protein, MeiP26, was initially described in the context of germline development [30], though it also functions in the soma (for example, [31]). In the oogenic germ cells, Mei-P26 begins to be expressed around the 16-cell cysts stage, restricting growth and proliferation [32]. Similarly to Brat, Mei-P26 seems also to be able to control nucleolar size and differentiation of the neuroblasts when overexpressed [32]. The underlying mechanism has been suggested to involve miRNAs, as both Mei-P26 and Brat are able to bind Argonaute1 (Ago1), which is a known component of the miRNA pathway [32]. Interestingly, Mei-P26 activates miRNA-dependent silencing of certain mRNAs, including brat, in GSCs [25,33], but inhibits the

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

miRNA pathway in differentiating germline cysts [32]. In fact, these context-dependent opposing roles translate into distinct biological roles as Mei-P26 is required for stem cell maintenance in GSCs and differentiation in GCs. This functional switch is suggested to involve binding of Mei-P26 to proteins specifically induced during differentiation, including Bam (BAg of Marbles, a pro-differentiation factor), Bgcn (Beningn Gonial Cell Neoplasm) and Sxl (SeX Lethal) [34]. Interestingly, the regulation of miRNA-dependent silencing has been also shown for the C. elegans Mei-P26 ortholog, NHL-2, which, similarly to Mei-P26, binds the Ago1 orthologs, ALG-1/2, enhancing miRNA activity [35,36]. While regulation of the miRNA pathway requires the NHL domain, Mei-P26 has been also suggested to act as an E3 enzyme in synaptic development [37]. Nevertheless, the underlying missense mutation is located in the NHL domain, suggesting a role in RNA-mediated post-transcriptional regulation.

55

also in the context of the degradation of postsynaptic density proteins, GKAP/SAPAP and Shank. The degradation of these factors is important for activity-dependent synaptic remodeling. Consistently, the loss of TRIM3 does not only prevent the degradation of postsynaptic proteins but also impacts the morphology of dendritic spines [50]. In addition to its role in protein degradation, TRIM3 was suggested to post-translationally mono-ubiquitinate a neuronal kinesin (KIF21B), modulating its velocity as a transporter [51]. Finally, TRIM3 was identified as a presumptive p53 target in human cells and mice and the TRIM3 protein was shown to regulate the intracellular trafficking of GABAA receptors, probably at a post-transcriptional level [52]. In line with the multitude of neuronal functions of this protein, elevated levels of TRIM3 have been found in the brain of schizophrenia patients [53]. 2.3. TRIM32

2.2. TRIM2 and TRIM3 TRIM2 (also known as NARF; Neural Activity-related Ring Finger protein) and TRIM3 (or BERP; Brain Expressed Ring finger Protein) are closely related mammalian proteins, which are predominantly expressed and function in the brain. TRIM2 was first implicated in neuronal plasticity in Mus musculus, where it interacts, via the NHL domain, with myosin V [38]. Additionally, by acting as an UbcH5adependent E3 ubiquitin ligase, TRIM2 prevents neurodegeneration by degrading NF-L (NeuroFilament Light subunit) [39]. A further neuronal role, related to the TRIM2-mediated ubiquitination of NFL, has been shown using cultured mouse hippocampal neurons: while the removal of TRIM2 causes the loss of neuronal polarity and axons, the overexpression of TRIM2 induces extra axons [40]. In addition to its roles in normal development, TRIM2 has been also implicated in tissue homeostasis. For example, TRIM2 is involved in the ubiquitination of the cell death-promoting factor Bim (Bcl-2-Interacting Mediator of cell death); this function provides neuroprotection and therefore increased tolerance to mild episodes of ischemia [41]. Consistent with its protective neuronal functions, TRIM2 alterations have been linked to human diseases. On one hand, an increase in the levels of TRIM2, possibly due to the down-regulation of two miRNAs (miR9 and miR181c), has been linked to the onset of neurodegenerative diseases such as AD (Alzheimer Disease; [42]). On the other hand, a childhood onset of axonal neuropathy has been connected to mutations affecting TRIM2: a point mutation in the CC domain affecting protein stability and another mutation resulting in a precocious STOP codon [43]. Similar to TRIM2, TRIM3 was first identified as an interactor of myosin V in the rat brain [44], where these factors, together with the endosome-associated proteins Hrs and Actinin-4, are present in a complex called CART (Cytoskeleton-Associated Recycling or Transport), which is important for the actin-dependent recycling of plasma membrane receptors [45]. The human TRIM3 gene is located in the chromosomal region 11p15, whose deletions are associated with several types of cancer, suggesting a potential tumor-suppressing role of TRIM3 [44]. Along the same lines, TRIM3 levels are low in hepatocellular carcinoma tissue samples [46]. However, TRIM3 has been mostly studied in the context of brain tumors [47]. For example, TRIM3 is deleted in around 25% of primary human gliomas [48] and low levels of TRIM3 correlate with a higher incidence and faster development of gliomas in mice [49]. In this context, TRIM3 has been proposed to function as a tumor suppressor through the binding to and inhibition of the CDK inhibitor p21, which promotes, rather than inhibits, proliferation in this context [49]. Soon after, the RING domain of TRIM3, acting as an E3 ubiquitin ligase via the interaction with the E2 enzyme UbcH5a, was shown to promote ubiquitination and degradation of p21 [16]. A role of TRIM3 as an E3 enzyme was earlier proposed

TRIM32, initially called HT2A, is a human protein first identified as a mediator of the biological activity of the lentiviral Tat protein [54]. Similarly to other TRIM-NHL proteins, TRIM32 has also been implicated in neuronal differentiation. An initial study showed that, in mice, TRIM32 promotes neuronal differentiation by targeting cMyc for degradation and, through binding to Ago1, by increasing the activity of the let-7 miRNA, [55]. Subsequent studies established a connection between TRIM32 and RAR␣ (Retinoic Acid Receptor ␣) (enhancing RAR␣ transcriptional activity; [56]), the protein kinase C ␨ (sequestering TRIM32 in the cytoplasm; [57]), Staufen2 [58] and p73 [59]. Apart from its roles in neurons, studies in cultured cells and/or mice demonstrated the importance of TRIM32 for myogenic differentiation [60] and muscle regrowth after atrophy [61]. Independently from its roles in development, TRIM32 has been linked to at least three human diseases, where mutations affecting distinct protein domains were identified. The Bardet-Biedl syndrome (BBS) is caused by mutations in the BB1 and the limb girdle muscular dystrophy 2H (LGMD2H) by mutations in the NHL repeats. The same mutations that cause LGMD2H also cause sarcotubular myopathy (STM) (Table 1). BBS is a pleiotropic ciliopathic disorder characterized by obesity, retinitis pigmentosa, polydactyly, hypogonadism and, in some cases, renal failure [62]. LGMD2H and STM, instead, specifically affect muscles, mostly of hips and shoulders, though, in some cases, the disease can cause cardiomyopathy [63]. The TRIM32 knock-out and knock-in mice (carrying the NHL mutation D489N, corresponding to the human D487N) have been both shown to recapitulate LGMD2H and STM defects [64,65], suggesting that the disease may result from a reduction in TRIM32 function rather than a specific loss of a molecular activity of the NHL domain [64]. However, a recent study described two patients with full deletions of TRIM32 who displayed no LGMD symptoms [66], which suggests that molecular etiology of LGDM is more complex than suggested by the mouse model studies. Apart from BBS, LGMD2H and STM, TRIM32 has been studied in the context of other ailments. In patients affected by psoriasis, TRIM32 has been found at high levels in epidermal lesions caused by aberrant regulation of keratinocytes [67]. The E3 ligase function of TRIM32 was shown to be important in the innate immune responses against RNA and DNA viruses [68]. Moreover, high levels of TRIM32 correlate with some neuronal disorders such as Alzheimer [69] and chronic stress-induced affective behaviors, where TRIM32 is supposed to act as a regulator of hyperactive behavior, anxiety and depression disorders [70]. Furthermore, TRIM32 has been suggested to act as a tumor suppressor [71] and pro-apoptotic factor [72]. However, in contradiction to this idea, elevated levels of TRIM32 occur in different models of epidermal carcinomas [73] and in human leukemic cell lines [74]. The detrimental effects of TRIM32 aberrations observed in the different diseases have been often explained by defects in the E3

56

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

ubiquitin ligase activity. In LGMD2H, protein substrates, whose deregulation might influence the onset and progression of the disease, include actin [75,76], tropomyosin, troponins and ␣-actinin [75], dysbindin [77] and c-Myc [60]. Moreover, TRIM32 has been suggested to act as a negative regulator of apoptosis, by blocking UVB-induced TNF␣ (Tumor Necrosis Factor ␣) apoptotic signaling through the ubiquitination and consequent degradation of Piasy (a protein inhibitor of activated STATs) [73,78]. Furthermore, TRIM32 has been suggested to regulate the ubiquitination and, therefore, degradation of the tumor suppressors Abi2 (ABl-Interactor 2) [79] and p53 [15]. 2.4. Abba and NHL-1 Abba (Another B-Box Affiliate, also known as Thin) is a D. melanogaster muscle-specific protein closely related to TRIM32 [80]. Abba localizes to the Z-disk in muscles and is important in maintaining the integrity of sarcomeric cytoarchitecture, both during development and, in adults, during muscle usage [81,82]. In absence of Abba, different factors important for myofibril stability and function (such as ␤-integrin, Spectrin, Talin and Vinculin) are mis-localized [82] and Abba has been shown to genetically interact with Z-disc genes (such as ␣-actinin, kettin/D-titin and mlp84B), which are important for the proper organization of myofibers [81]. Although the precise molecular mechanism remains to be determined, Abba has been hypothesized to stabilize a protein complex constituted by the above-mentioned Z-disk components, thus ensuring muscle integrity [81]. Even less is known about the C. elegans NHL-1, which, similarly to Abba, seems to be mainly expressed in muscles [83]. Despite that, NHL-1 has been only studied in chemosensory neurons, where NHL-1 allows cross-tissue communication in response to infections by pathogenic bacteria and to proteotoxicity [84]. How precisely NHL-1 exerts this interesting function remains to be determined. 2.5. Wech Although not extensively studied, the D. melanogaster Wech (also known as Dappled) is an interesting TRIM-NHL protein. Similar to Brat, it lacks the RING domain and its expression is directly repressed by the let-7 miRNAs [80]. As will become apparent from the next paragraph, let-7-dependent regulation of lin-41 orthologs is conserved. As the conservation between Wech and LIN-41 is relatively high, the close link with let-7 raises the possibility of a common ancestor regulated by let-7. Similar to some other TRIM-NHL proteins, the main function of Wech appears to be in muscles, particularly in the regulation of integrin-cytoskeleton connection during embryonic muscle attachment [85]. Specifically, Wech has been shown to directly interact with the linker proteins Talin and ILK (Integrin-Linked-Kinase), which connect the integrin transmembrane receptors to the cytoskeleton. This interaction is dependent on BBs, CC and, probably to a lower extent, NHL repeats [85]. 2.6. LIN-41 and TRIM71 LIN-41 (LINeage defective 41) was initially uncovered in C. elegans as a member of the so-called heterochronic pathway. This pathway consists of a cascade of regulatory events, which temporally control the timing of developmental transitions in certain somatic tissues [86]. Specifically, heterochronic genes control the proliferation versus differentiation decision in epidermal cells called the seam cells. Mutations in heterochronic genes either delay or speed up seam cell differentiation [87,88]. In this context, the lin-41 mRNA was identified as a direct target of the let-7 miRNA [88,89], which inhibits lin-41 translation and promotes its

degradation via specific let-7 binding sites (LBSs) in the lin-41 3’UTR [90]. Remarkably, the let-7-mediated repression of lin-41 is conserved from worms to vertebrates [91–95]. This is why the interest in lin-41 has been for a long time let-7 miRNA-centric. However, a number of papers have been recently published, providing new insights into different aspects of LIN-41 biology. These include a germline role for LIN-41 in preventing an untimely oocyte-toembryo transition [8], which may involve translational repression of key cell cycle factors [96] and a role in axon regeneration [97]. The latter role is restricted to growing neurons, as in terminally differentiated neurons lin-41 mRNA is repressed by let-7 [97]. In addition to C. elegans, LIN-41 orthologs, called LIN-41 or TRIM71, have been shown to play critical developmental roles in several other species. During embryogenesis, LIN-41/TRIM71 is essential for chick and murine limb development [93], murine neural tube closure [98], proper timing of zebrafish embryonic development [94] and maintenance of murine neuronal progenitors [99]. In disease, high levels of LIN-41 have been linked to hepatocellular carcinoma [100] and myxoid liposarcoma [101]. The murine LIN-41/TRIM71 has been reported to act in the FGF (Fibroblast Growth Factor) signaling pathway [93,99]. In this context, LIN-41 has been suggested to act as an E3 ubiquitin ligase to mediate ubiquitination (presumably mono-) and stabilization of SHCBP1 (SHC SH2-Binding Protein 1), one of the effectors of the FGF pathway. In mammalian cells, LIN-41 is enriched in P-bodies [102,103], which are cytoplasmic protein/RNA agglomerates involved in different aspects of mRNA regulation (e.g., mRNA turnover). Accordingly, LIN-41 has been shown to interact with components of the RISC (RNA-induced silencing complex) in HeLa and EC (Embryonic Carcinoma) cells and to act as an E3 enzyme (in vitro and in vivo), interfering, in this case, with miRNA activity [103]. Specifically, the LIN-41 CC domain was shown to recruit and facilitate Ago2 via interaction with the E2 conjugating enzyme UbcH5a. In this way, LIN-41 was suggested to cooperate with LIN28 in suppressing let-7 activity [103]. However, the LIN-41-dependent ubiquitination and degradation of Ago2 have not been confirmed in another study [99]. Without much direct evidence, a hypothesis was put forth that LIN-41 antagonizes miRNA activity through its E3 activity, ubiquitinating and reducing the levels of Ago1/2. This, in turn, would increase the levels of LIN28B and c-Myc, both of which are otherwise repressed by let-7 [100]. By contrast, in a more recent publication, LIN-41 has been shown to mediate ubiquitination of LIN28B, allowing proper let-7 maturation and thus enhancing let-7 mediated regulation [104]. Besides the RING domain, the NHL domain of LIN-41/TRIM71 has also been implicated in miRNA regulation. In ES (Embryonic Stem) cells, a miRNA-dependent interaction of LIN-41/TRIM71 with Dicer and different Ago proteins was shown to enhance the miRNA pathway activity [97,102]. The authors proposed that LIN-41/TRIM71 interacts with Ago2 through the NHL domain mediated binding to two miRNAs, miR-302 and miR-290. This interaction was proposed to promote ES cell proliferation by repressing translation of the Cdkn1a mRNA, which encodes a key cell cycle regulator [102]. Clearly additional work is needed before the complicated relation between LIN-41, its E3 ligase activity and miRNAs can be resolved. Interestingly, the C. elegans LIN-41 has been recently shown to lack a functional RING domain [8], suggesting a ubiquitinationindependent mode of action. Indeed, LIN-41 has been regarded from the outset as a post-transcriptional regulator. In the C. elegans seam cells and neurons, LIN-41 is thought to bind and repress the lin-29 mRNA, which encodes a transcriptional effector of the let7/lin-41 regulatory axis [89]. In germ cells, LIN-41 must function through a different target(s) [8] and cdc-25.3 mRNA has been proposed as a candidate [96]. It has been recently shown in mammalian cells that LIN-41/TRIM71 can be used instead of c-Myc in the canonical “reprogramming” mixture additionally containing Oct4, Sox2,

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

and Klf4, to convert fibroblasts into iPS (induced Pluripotent Stem) cells [105,106]. In a previous study, a direct binding of c-Myc to the lin-41 promoter, enhancing lin-41 expression, was demonstrated [100], suggesting LIN-41/TRIM71 as a c-Myc effector. In the context of iPS cells, LIN-41/TRIM71 has been proposed to function by repressing the translation of the pro-differentiation TF EGR1 [105]. However, whether this function of LIN-41/TRIM71 requires the NHL domain remains to be tested. In the C. elegans LIN-41, a number of residue substitutions in the NHL domain compromise protein function [8,89,96]. A major step towards solving the molecular function of the NHL domain has been made by Loedige and collaborators [13]. Firstly, they showed that LIN-41/TRIM71 can bind and regulate specific mRNAs via their 3’UTRs and examined the relative roles of LIN-41/TRIM71 domains in mRNA regulation. From the TRIM domain, the CC together with the filamin domains were proposed to recruit co-factors mediating the actual mRNA silencing, whereas the NHL repeats alone were suggested to mediate the binding to mRNAs [13]. How the LIN-41/TRIM71 binding to mRNA affects the fate of the transcript remains, however, unknown. 3. Conclusions and remarks From the evidence summarized here emerges a view of two main molecular functions of TRIM-NHL proteins: protein ubiquitination and mRNA regulation. In principle, these two activities could be used to the same end, i.e., RNA binding might bring the E3 ubiquitin ligase into the proximity of other RBPs, whose degradation would impact mRNA stability and/or translation. Effecting mRNA fate through such a mechanism has been previously observed, in the case of human MEX-3 RBPs [107], but whether any TRIM-NHL protein can function in this way remains unclear. In fact, some TRIM-NHL proteins (Brat and Wech) lack the entire RING domain and the nematode LIN-41 apparently contains a non-functional RING domain. Perhaps the E3 ligase activity, shared by an ancestral TRIM-NHL protein, was lost from those proteins because they evolved a different mechanism of action. Alternatively, the E3 activity was “outsourced” to another protein, with which the E3-less TRIM-NHL proteins might interact. Additionally, as described for TRIM32, mutations affecting different domains can have unique pathological outcomes, suggesting that, in at least some proteins, different domains may function independently from each other. Intriguingly, though a few family members differ in the TRIM domain as discussed above, the NHL domain, with its positively charged surface interacting with RNA, is highly conserved in all family members [18]. This conservation suggests that the RNA regulation may be a unifying theme among the family members. Therefore, understanding the RNA-binding specificity of TRIM-NHL proteins and the precise mechanisms by which these proteins affect their mRNA targets are the main goals for the future research. Acknowledgements Parts of this review have been reproduced from C.T.’s PhD thesis. We thank Joerg Betschinger and Heinz Gut for comments on the manuscript. References [1] Reymond A, Meroni G, Fantozzi A, Merla G, Cairo S, Luzi L, Riganelli D, Zanaria E, Messali S, Cainarca S, Guffanti A, Minucci S, Pelicci PG, Ballabio A. The tripartite motif family identifies cell compartments. EMBO J 2001;20(9):2140–51. [2] Short KM, Cox TC. Subclassification of the RBCC/TRIM superfamily reveals a novel motif necessary for microtubule binding. J. Biol. Chem 2006;281(13):8970–80. [3] Meroni G, Diez-Roux G. TRIM/RBCC, a novel class of ‘single protein RING finger’ E3 ubiquitin ligases. Bioessays 2005;27(11):1147–57.

57

[4] Barlow PN, Luisi B, Milner A, Elliott M, Everett R. Structure of the C3HC4 domain by 1H-nuclear magnetic resonance spectroscopy. A new structural class of zinc-finger. J. Mol. Biol 1994;237(2):201–11. [5] Borden KL, Lally JM, Martin SR, O’Reilly NJ, Etkin LD, Freemont PS. Novel topology of a zinc-binding domain from a protein involved in regulating early Xenopus development. EMBO J 1995;14(23):5947–56. [6] Freemont PS. The RING finger. A novel protein sequence motif related to the zinc finger. Ann. N.Y. Acad. Sci 1993;684:174–92. [7] Budhidarmo R, Nakatani Y, Day CL. RINGs hold the key to ubiquitin transfer. Trends Biochem. Sci 2012;37:58–65. [8] Tocchini C, Keusch JJ, Miller SB, Finger S, Gut H, Stadler MB, Ciosk R. The TRIM-NHL protein LIN-41 controls the onset of developmental plasticity in Caenorhabditis elegans. PLoS Genet 2014;10(8):e1004533, http://dx.doi.org/10.1371/journal.pgen.1004533. [9] Massiah MA, Matts JA, Short KM, Simmons BN, Singireddy S, Yi Z, Cox TC. Solution structure of the MID1 B-box2 CHC(D/C)C(2)H(2) zinc-binding domain: insights into an evolutionarily conserved RING fold. J. Mol. Biol 2007;369(1):1–10. [10] Micale L, Chaignat E, Fusco C, Reymond A, Merla G. The tripartite motif: structure and function. Adv. Exp. Med. Biol 2012;770:11–25. [11] Tao H, Simmons BN, Singireddy S, Jakkidi M, Short KM, Cox TC, Massiah MA. Structure of the MID1 tandem B-boxes reveals an interaction reminiscent of intermolecular ring heterodimers. Biochemistry 2008;47(8):2450–7, http://dx.doi.org/10.1021/bi7018496. [12] Lupas A. Coiled coils: new structures and new functions. Trends Biochem. Sci 1996;21(10):375–82. [13] Loedige I, Gaidatzis D, Sack R, Meister G, Filipowicz W. The mammalian TRIM-NHL protein TRIM71/LIN-41 is a repressor of mRNA function. Nucleic Acids Res 2013;41(1):518–32, http://dx.doi.org/10.1093/nar/gks1032. [14] Bork P, Holm L, Sander C. The immunoglobulin fold. Structural classification, sequence patterns and common core. J. Mol. Biol 1994;242:309–20. [15] Liu J, Zhang C, Wang XL, Ly P, Belyi V, Xu-Monette ZY, Young KH, Hu W, Feng Z. E3 ubiquitin ligase TRIM32 negatively regulates tumor suppressor p53 to promote tumorigenesis. Cell Death Differ 2014;21(11):1792–804, http://dx.doi.org/10.1038/cdd.2014.121. [16] Raheja R, Liu Y, Hukkelhoven E, Yeh N, Koff A. The ability of TRIM3 to induce growth arrest depends on RING-dependent E3 ligase activity. Biochem. J 2014;458(3):537–45, http://dx.doi.org/10.1042/BJ20131288. [17] Edwards TA, Wilkinson BD, Wharton RP, Aggarwal AK. Model of the brain tumor-Pumilio translation repressor complex. Genes Dev 2003;17: 2508–13. [18] Loedige I, Stotz M, Qamar S, Kramer K, Hennig J, Schubert T, Löffler P, Längst G, Merkl R, Urlaub H, Meister G. The NHL domain of BRAT is an RNA-binding domain that directly contacts the hunchback mRNA for regulation. Genes Dev 2014;28(7):749–64, http://dx.doi.org/10.1101/gad.236513.113. [19] Slack FJ, Ruvkun G. A novel repeat domain that is often associated with RING finger and B-box motifs. Trends Biochem. Sci 1998;23(12):474–5. [20] Arama E, Dickman D, Kimchie Z, Shearn A, Lev Z. Mutations in the beta-propeller domain of the Drosophila brain tumor (brat) protein induce neoplasm in the larval brain. Oncogene 2000;19(33):3706–16. [21] Betschinger J, Mechtler K, Knoblich JA. Asymmetric segregation of the tumor suppressor brat regulates self-renewal in Drosophila neural stem cells. Cell 2006;124:1241–53. [22] Frank DJ, Edgar BA, Roth MB. The Drosophila melanogaster gene brain tumor negatively regulates cell growth and ribosomal RNA synthesis. Development 2002;129:399–407. [23] Frank DJ, Roth MB. ncl-1 is required for the regulation of cell size and ribosomal RNA synthesis in Caenorhabditis elegans. J. Cell. Biol 1998;140(6):1321–9. [24] Loop T, Leemans R, Stiefel U, Hermida L, Egger B, Xie F, Primig M, Certa U, Fischbach KF, Reichert H, Hirth F. Transcriptional signature of an adult brain tumor in Drosophila. BMC Genomics 2004;5(1):24. [25] Harris RE, Pargett M, Sutcliffe C, Umulis D, Ashe HL. Brat promotes stem cell differentiation via control of a bistable switch that restricts BMP signaling. Dev. Cell 2011;20(1):72–83, http://dx.doi.org/10.1016/j.devcel.2010.11.019. [26] Shi W, Chen Y, Gan G, Wang D, Ren J, Wang Q, Xu Z, Xie W, Zhang YQ. Brain tumor regulates neuromuscular synapse growth and endocytosis in Drosophila by suppressing mad expression. J. Neurosci 2013;33(30):12352–63, http://dx.doi.org/10.1523/JNEUROSCI.0386-13.2013. [27] Sonoda J, Wharton RP. Drosophila brain tumor is a translational repressor. Genes Dev 2001;15(6):762–73. [28] Laver JD, Li X, Ray D, Cook KB, Hahn NA, Nabeel-Shah S, Kekis M, Luo H, Marsolais AJ, Fung KY, Hughes TR, Westwood JT, Sidhu SS, Morris Q, Lipshitz HD, Smibert CA. Brain tumor is a sequence-specific RNA-binding protein that directs maternal mRNA clearance during the Drosophila maternal-to-zygotic transition. Genome Biol 2015;16(1):94. [29] Komori H, Xiao Q, McCartney BM, Lee CY. Brain tumor specifies intermediate progenitor cell identity by attenuating ␤-catenin/Armadillo activity. Development 2014;141(1):51–62, http://dx.doi.org/10.1242/dev.099382. [30] Page SL, McKim KS, Deneen B, Van Hook TL, Hawley RS. Genetic studies of mei-P26 reveal a link between the processes that control germ cell proliferation in both sexes and those that control meiotic exchange in Drosophila. Genetics 2000;155(4):1757–72.

58

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

[31] Ferreira A, Boulan L, Perez L, Milán M. Mei-P26 mediates tissue-specific responses to the Brat tumor suppressor and the dMyc proto-oncogene in Drosophila. Genetics 2014;198(1):249–58, http://dx.doi.org/10.1534/genetics.114.167502. [32] Neumüller RA, Betschinger J, Fischer A, Bushati N, Poernbacher I, Mechtler K, Cohen SM, Knoblich JA. Mei-P26 regulates microRNAs and cell growth in the Drosophila ovarian stem cell lineage. Nature 2008;454(7201):241–5, http://dx.doi.org/10.1038/nature07014. [33] Li Y, Maines JZ, Tastan OY, McKearin DM, Buszczak M. Mei-P26 regulates the maintenance of ovarian germline stem cells by promoting BMP signaling. Development 2012;139(9):1547–56, http://dx.doi.org/10.1242/dev.077412. [34] Li Y, Zhang Q, Carreira-Rosario A, Maines JZ, McKearin DM, Buszczak M. Mei-p26 cooperates with Bam, Bgcn and Sxl to promote early germline development in the Drosophila ovary. PLoS One 2013;8(3):e58301, http://dx.doi.org/10.1371/journal.pone.0058301. [35] Hammell CM, Lubin I, Boag PR, Blackwell TK, Ambros V. nhl-2 Modulates microRNA activity in Caenorhabditis elegans. Cell 2009;136(5):926–38, http://dx.doi.org/10.1016/j.cell.2009.01.053. [36] Karp X, Ambros V. Dauer larva quiescence alters the circuitry of microRNA pathways regulating cell fate progression in C. elegans. Development 2012;139(12):2177–86, http://dx.doi.org/10.1242/dev.075986. [37] Glasscock E, Singhania A, Tanouye MA. The mei-P26 gene encodes a RING finger B-box coiled-coil-NHL protein that regulates seizure susceptibility in Drosophilia. Genetics 2005;170(4):1677–89. [38] Ohkawa N, Kokura K, Matsu-Ura T, Obinata T, Konishi Y, Tamura TA. Molecular cloning and characterization of neural activity-related RING finger protein (NARF): a new member of the RBCC family is a candidate for the partner of myosin V. J. Neurochem 2001;78(1):75–87. [39] Balastik M, Ferraguti F, Pires-da Silva A, Lee TH, Alvarez-Bolado G, Lu KP, Gruss P. Deficiency in ubiquitin ligase TRIM2 causes accumulation of neurofilament light chain and neurodegeneration. Proc. Natl. Acad. Sci. U.S.A 2008;105(33):12016–21, http://dx.doi.org/10.1073/pnas.0802261105. [40] Khazaei MR, Bunk EC, Hillje AL, Jahn HM, Riegler EM, Knoblich JA, Young P, Schwamborn JC. The E3-ubiquitin ligase TRIM2 regulates neuronal polarization. J. Neurochem 2011;117(1):29–37, http://dx.doi.org/10.1111/j.1471-4159.2010.06971.x. [41] Thompson S, Pearson AN, Ashley MD, Jessick V, Murphy BM, Gafken P, Henshall DC, Morris KT, Simon RP, Meller R. Identification of a novel Bcl-2-interacting mediator of cell death (Bim) E3 ligase, tripartite motif-containing protein 2 (TRIM2), and its role in rapid ischemic tolerance-induced neuroprotection. J. Biol. Chem 2011;286(22):19331–9, http://dx.doi.org/10.1074/jbc.M110.197707. [42] Schonrock N, Humphreys DT, Preiss T, Götz J. Target gene repression mediated by miRNAs miR-181c and miR-9 both of which are down-regulated by amyloid-␤. J. Mol. Neurosci 2012;46(2):324–35, http://dx.doi.org/10.1007/s12031-011-9587-2. [43] Ylikallio E, Pöyhönen R, Zimon M, De Vriendt E, Hilander T, Paetau A, Jordanova A, Lönnqvist T, Tyynismaa H. Deficiency of the E3 ubiquitin ligase TRIM2 in early-onset axonal neuropathy. Hum. Mol. Genet 2013;22(15):2975–83, http://dx.doi.org/10.1093/hmg/ddt149. [44] El-Husseini AE, Fretier P, Vincent SR. Cloning and characterization of a gene (RNF22) encoding a novel brain expressed ring finger protein (BERP) that maps to human chromosome 11p15.5. Genomics 2001;71(3):363–7. [45] Yan Q, Sun W, Kujala P, Lotfi Y, Vida TA, Bean AJ. CART: an Hrs/actinin-4/BERP/myosin V protein complex required for efficient receptor recycling. Mol. Biol. Cell 2005;16(5):2470–82. [46] Chao J, Zhang XF, Pan QZ, Zhao JJ, Jiang SS, Wang Y, Zhang JH, Xia JC. Decreased expression of TRIM3 is associated with poor prognosis in patients with primary hepatocellular carcinoma. Med. Oncol 2014;31(8):102, http://dx.doi.org/10.1007/s12032-014-0102-9. [47] Chen D, Wu C, Zhao S, Geng Q, Gao Y, Li X, Zhang Y, Wang Z. Three RNA binding proteins form a complex to promote differentiation of germline stem cell lineage in Drosophila. PLoS Genet 2014;10(11):e1004797, http://dx.doi.org/10.1371/journal.pgen.1004797. [48] Boulay JL, Stiefel U, Taylor E, Dolder B, Merlo A, Hirth F. Loss of heterozygosity of TRIM3 in malignant gliomas. BMC Cancer 2009;9:71, http://dx.doi.org/10.1186/1471-2407-9-71. [49] Liu Y, Raheja R, Yeh N, Ciznadija D, Pedraza AM, Ozawa T, Hukkelhoven E, Erdjument-Bromage H, Tempst P, Gauthier NP, Brennan C, Holland EC, Koff A. TRIM3, a tumor suppressor linked to regulation of p21(Waf1/Cip1.). Oncogene 2014;33(3):308–15, http://dx.doi.org/10.1038/onc.2012.596. [50] Hung AY, Sung CC, Brito IL, Sheng M. Degradation of postsynaptic scaffold GKAP and regulation of dendritic spine morphology by the TRIM3 ubiquitin ligase in rat hippocampal neurons. PLoS One 2010;5(3):e9842, http://dx.doi.org/10.1371/journal.pone.0009842. [51] Laboute E, France J, Trouve P, Puig PL, Boireau M, Blanchard A. Rehabilitation and leucine supplementation as possible contributors to an athlete’s muscle strength in the reathletization phase following anterior cruciate ligament surgery. Ann. Phys. Rehabil. Med 2013;56(2):102–12, http://dx.doi.org/10.1016/j.rehab.2012.11.002. [52] Cheung CC, Yang C, Berger T, Zaugg K, Reilly P, Elia AJ, Wakeham A, You-Ten A, Chang N, Li L, Wan Q, Mak TW. Identification of BERP (brain-expressed RING finger protein) as a p53 target gene that modulates seizure

susceptibility through interacting with GABA(A) receptors. Proc. Natl. Acad. Sci. U.S.A 2010;107(26):11883–8, http://dx.doi.org/10.1073/pnas.1006529107. [53] Martins-de-Souza D, Gattaz WF, Schmitt A, Maccarrone G, Hunyadi-Gulyás E, Eberlin MN, Souza GH, Marangoni S, Novello JC, Turck CW, Dias-Neto E. Proteomic analysis of dorsolateral prefrontal cortex indicates the involvement of cytoskeleton, oligodendrocyte, energy metabolism and new potential markers in schizophrenia. J. Psychiatr. Res 2009;43(11):978–86, http://dx.doi.org/10.1016/j.jpsychires.2008.11.006. [54] Fridell RA, Harding LS, Bogerd HP, Cullen BR. Identification of a novel human zinc finger protein that specifically interacts with the activation domain of lentiviral Tat proteins. Virology 1995;209(2):347–57. [55] Schwamborn JC, Berezikov E, Knoblich JA. The TRIM-NHL protein TRIM32 activates microRNAs and prevents self-renewal in mouse neural progenitors. Cell 2009;136(5):913–25, http://dx.doi.org/10.1016/j.cell.2008.12.024. [56] Sato T, Okumura F, Kano S, Kondo T, Ariga T, Hatakeyama S. TRIM32 promotes neural differentiation through retinoic acid receptor-mediated transcription. J. Cell Sci 2011;124(Pt 20):3492–502, http://dx.doi.org/10.1242/jcs.088799. [57] Hillje AL, Worlitzer MM, Palm T, Schwamborn JC. Neural stem cells maintain their stemness through protein kinase C (-mediated inhibition of TRIM32. Stem Cells 2011;29(9):1437–47, http://dx.doi.org/10.1002/stem.687. [58] Kusek G, Campbell M, Doyle F, Tenenbaum SA, Kiebler M, Temple S. Asymmetric segregation of the double-stranded RNA binding protein Staufen2 during mammalian neural stem cell divisions promotes lineage progression. Cell Stem Cell 2012;11(4):505–16, http://dx.doi.org/10.1016/j.stem.2012.06.006. [59] Gonzalez-Cano L, Hillje AL, Fuertes-Alvarez S, Marques MM, Blanch A, Ian RW, Irwin MS, Schwamborn JC, Marín MC. Regulatory feedback loop between TP73 and TRIM32. Cell Death Dis 2013;4:e704, http://dx.doi.org/10.1038/cddis.2013.224. [60] Nicklas S, Otto A, Wu X, Miller P, Stelzer S, Wen Y, Kuang S, Wrogemann K, Patel K, Ding H, Schwamborn JC. TRIM32 regulates skeletal muscle stem cell differentiation and is necessary for normal adult muscle regeneration. PLoS One 2012;7(1):e30445, http://dx.doi.org/10.1371/journal.pone.0030445. [61] Kudryashova E, Kramerova I, Spencer MJ. Satellite cell senescence underlies myopathy in a mouse model of limb-girdle muscular dystrophy 2H. J. Clin. Invest 2012;122(5):1764–76, http://dx.doi.org/10.1172/JCI59581. [62] Beales PL, Elcioglu N, Woolf AS, Parker D, Flinter FA. New criteria for improved diagnosis of Bardet-Biedl syndrome: results of a population survey. J. Med. Genet 1999;36(6):437–46. [63] Nigro V, Aurino S, Piluso G. Limb girdle muscular dystrophies: update on genetic diagnosis and therapeutic approaches. Curr. Opin. Neurol 2011;24(5):429–36, http://dx.doi.org/10.1097/WCO.0b013e32834a38d. [64] Kudryashova E, Struyk A, Mokhonova E, Cannon SC, Spencer MJ. The common missense mutation D489N in TRIM32 causing limb girdle muscular dystrophy 2H leads to loss of the mutated protein in knock-in mice resulting in a Trim32-null phenotype. Hum. Mol. Genet 2011;20(20):3925–32, http://dx.doi.org/10.1093/hmg/ddr311. [65] Kudryashova E, Wu J, Havton LA, Spencer MJ. Deficiency of the E3 ubiquitin ligase TRIM32 in mice leads to a myopathy with a neurogenic component. Hum. Mol. Genet 2009;18(7):1353–67, http://dx.doi.org/10.1093/hmg/ddp036. [66] Nectoux J, de Cid R, Baulande S, Leturcq F, Urtizberea JA, Penisson-Besnier I, Nadaj-Pakleza A, Roudaut C, Criqui A, Orhant L, Peyroulan D, Ben Yaou R, Nelson I, Cobo AM, Arné-Bes MC, Uro-Coste E, Nitschke P, Claustres M, Bonne G, Lévy N, Chelly J, Richard I, Cossée M. Detection of TRIM32 deletions in LGMD patients analyzed by a combined strategy of CGH array and massively parallel sequencing. Eur. J. Hum. Genet 2014, http://dx.doi.org/10.1038/ejhg.2014.223. [67] Liu Y, Lagowski JP, Gao S, Raymond JH, White CR, Kulesz-Martin MF. Regulation of the psoriatic chemokine CCL20 by E3 ligases Trim32 and Piasy in keratinocytes. J. Invest. Dermatol 2010;130(5):1384–90, http://dx.doi.org/10.1038/jid.2009.416. [68] Zhang J, Hu MM, Wang YY, Shu HB. TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination. J. Biol. Chem 2012;287(34):28646–55, http://dx.doi.org/10.1074/jbc.M112.362608. [69] Yokota T, Mishra M, Akatsu H, Tani Y, Miyauchi T, Yamamoto T, Kosaka K, Nagai Y, Sawada T, Heese K. Brain site-specific gene expression analysis in Alzheimer’s disease patients. Eur. J. Clin. Invest 2006;36(11): 820–30. [70] Ruan CS, Wang SF, Shen YJ, Guo Y, Yang CR, Zhou FH, Tan LT, Zhou L, Liu JJ, Wang WY, Xiao ZC, Zhou XF. Deletion of TRIM32 protects mice from anxiety- and depression-like behaviors under mild stress. Eur. J. Neurosci 2014;40(4):2680–90, http://dx.doi.org/10.1111/ejn.12618. [71] Izumi H, Kaneko Y. Trim32 facilitates degradation of MYCN on spindle poles and induces asymmetric cell division in human neuroblastoma cells. Cancer Res 2014;74(19):5620–30, http://dx.doi.org/10.1158/0008-5472.CAN-14-0169. [72] Ryu YS, Lee Y, Lee KW, Hwang CY, Maeng JS, Kim JH, Seo YS, You KH, Song B, Kwon KS. TRIM32 protein sensitizes cells to tumor necrosis factor (TNF()-induced apoptosis via its RING domain-dependent E3 ligase activity

C. Tocchini, R. Ciosk / Seminars in Cell & Developmental Biology 47–48 (2015) 52–59

[73]

[74]

[75]

[76]

[77]

[78]

[79]

[80]

[81]

[82]

[83]

[84]

[85]

[86] [87] [88]

[89]

against X-linked inhibitor of apoptosis (XIAP). J. Biol. Chem 2011;286(29):25729–38, http://dx.doi.org/10.1074/jbc.M111.241893. Horn EJ, Albor A, Liu Y, El-Hizawi S, Vanderbeek GE, Babcock M, Bowden GT, Hennings H, Lozano G, Weinberg WC, Kulesz-Martin M. RING protein Trim32 associated with skin carcinogenesis has anti-apoptotic and E3-ubiquitin ligase properties. Carcinogenesis 2004;25(2):157–67. Sato T, Okumura F, Iguchi A, Ariga T, Hatakeyama S. TRIM32 promotes retinoic acid receptor (-mediated differentiation in human promyelogenous leukemic cell line HL60. Biochem. Biophys. Res. Commun 2012;417(1):594–600, http://dx.doi.org/10.1016/j.bbrc.2011.12.012. Cohen S, Zhai B, Gygi SP, Goldberg AL. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J. Cell Biol 2012;198(4):575–89, http://dx.doi.org/10.1083/jcb.201110067. Kudryashova E, Kudryashov D, Kramerova I, Spencer MJ. Trim32 is a ubiquitin ligase mutated in limb girdle muscular dystrophy type 2H that binds to skeletal muscle myosin and ubiquitinates actin. J. Mol. Biol 2005;354(2):413–24. Locke M, Tinsley CL, Benson MA, Blake DJ. TRIM32 is an E3 ubiquitin ligase for dysbindin. Hum. Mol. Genet 2009;18(13):2344–58, http://dx.doi.org/10.1093/hmg/ddp167. Albor A, El-Hizawi S, Horn EJ, Laederich M, Frosk P, Wrogemann K, Kulesz-Martin M. The interaction of Piasy with Trim32, an E3-ubiquitin ligase mutated in limb-girdle muscular dystrophy type 2H, promotes Piasy degradation and regulates UVB-induced keratinocyte apoptosis through NFkappaB. J. Biol. Chem 2006;281(35):25850–66. Kano S, Miyajima N, Fukuda S, Hatakeyama S. Tripartite motif protein 32 facilitates cell growth and migration via degradation of Abl-interactor 2. Cancer Res 2008;68(14):5572–80, http://dx.doi.org/10.1158/0008-5472.CAN-07-6231. O’Farrell F, Esfahani SS, Engström Y, Kylsten P. Regulation of the Drosophila lin-41 homologue dappled by let-7 reveals conservation of a regulatory mechanism within the LIN-41 subclade. Dev. Dyn 2008;237(1):196–208. Domsch K, Ezzeddine N, Nguyen HT. Abba is an essential TRIM/RBCC protein to maintain the integrity of sarcomeric cytoarchitecture. J. Cell Sci 2013;126(Pt 15):3314–23, http://dx.doi.org/10.1242/jcs.122366. LaBeau-DiMenna EM, Clark KA, Bauman KD, Parker DS, Cripps RM, Geisbrecht ER. Thin, a Trim32 ortholog, is essential for myofibril stability and is required for the integrity of the costamere in Drosophila. Proc. Natl. Acad. Sci. U.S.A 2012;109(44):17983–8, http://dx.doi.org/10.1073/pnas.1208408109. McKay SJ, Johnsen R, Khattra J, Asano J, Baillie DL, Chan S, Dube N, Fang L, Goszczynski B, Ha E, Halfnight E, Hollebakken R, Huang P, Hung K, Jensen V, Jones SJ, Kai H, Li D, Mah A, Marra M, McGhee J, Newbury R, Pouzyrev A, Riddle DL, Sonnhammer E, Tian H, Tu D, Tyson JR, Vatcher G, Warner A, Wong K, Zhao Z, Moerman DG. Gene expression profiling of cells, tissues, and developmental stages of the nematode C. elegans. Cold Spring Harb. Symp. Quant. Biol 2003;68:159–69. Volovik Y, Moll L, Marques FC, Maman M, Bejerano-Sagie M, Cohen E. Differential regulation of the heat shock factor 1 and DAF-16 by neuronal nhl-1 in the nematode C. elegans. Cell Rep 2014;9(6):2192–205, http://dx.doi.org/10.1016/j.celrep.2014.11.028. Löer B, Bauer R, Bornheim R, Grell J, Kremmer E, Kolanus W, Hoch M. The NHL-domain protein Wech is crucial for the integrin-cytoskeleton link. Nat. Cell Biol 2008;10(4):422–8, http://dx.doi.org/10.1038/ncb1704. Ambros V. A hierarchy of regulatory genes controls a larva-to-adult developmental switch in C. elegans. Cell 1989;57(1):49–57. Ambros V, Horvitz HR. Heterochronic mutants of the nematode Caenorhabditis elegans. Science 1984;226(4673):409–16. Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, Horvitz HR, Ruvkun G. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000;403(6772):901–6. Slack FJ, Basson M, Liu Z, Ambros V, Horvitz HR, Ruvkun G. The lin-41 RBCC gene acts in the C. elegans heterochronic pathway between the let-7 regulatory RNA and the LIN-29 transcription factor. Mol. Cell 2000;5(4):659–69.

59

[90] Vella MC, Choi EY, Lin SY, Reinert K, Slack FJ. The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3’UTR. Genes Dev 2004;18(2):132–7. [91] Ecsedi M, Grosshans H. LIN-41/TRIM71: emancipation of a miRNA target. Genes Dev 2013;27(6):581–9, http://dx.doi.org/10.1101/gad.207266.112. [92] Kanamoto T, Terada K, Yoshikawa H, Furukawa T. Cloning and regulation of the vertebrate homologue of lin-41 that functions as a heterochronic gene in Caenorhabditis elegans. Dev. Dyn 2006;235(4):1142–9. [93] Lancman JJ, Caruccio NC, Harfe BD, Pasquinelli AE, Schageman JJ, Pertsemlidis A, Fallon JF. Analysis of the regulation of lin-41 during chick and mouse limb development. Dev. Dyn 2005;234(4):948–60. [94] Lin YC, Hsieh LC, Kuo MW, Yu J, Kuo HH, Lo WL, Lin RJ, Yu AL, Li WH. Human TRIM71 and its nematode homologue are targets of let-7 microRNA and its zebrafish orthologue is essential for development. Mol. Biol. Evol 2007;24(11):2525–34. [95] Schulman BR, Esquela-Kerscher A, Slack FJ. Reciprocal expression of lin-41 and the microRNAs let-7 and mir-125 during mouse embryogenesis. Dev. Dyn 2005;234(4):1046–54. [96] Spike CA, Coetzee D, Eichten C, Wang X, Hansen D, Greenstein D. The TRIM-NHL protein LIN-41 and the OMA RNA-binding proteins antagonistically control the prophase-to-metaphase transition and growth of Caenorhabditis elegans oocytes. Genetics 2014;198(4):1535–58, http://dx.doi.org/10.1534/genetics.114.168831. [97] Zou Y, Chiu H, Zinovyeva A, Ambros V, Chuang CF, Chang C. Developmental decline in neuronal regeneration by the progressive change of two intrinsic timers. Science 2013;340(6130):372–6, http://dx.doi.org/10.1126/science.1231321. [98] Maller Schulman BR, Liang X, Stahlhut C, DelConte C, Stefani G, Slack FJ. The let-7 microRNA target gene, Mlin41/Trim71 is required for mouse embryonic survival and neural tube closure. Cell Cycle 2008;7(24):3935–42. [99] Chen J, Lai F, Niswander L. The ubiquitin ligase mLin41 temporally promotes neural progenitor cell maintenance through FGF signaling. Genes Dev 2012;26(8):803–15, http://dx.doi.org/10.1101/gad.187641.112. [100] Chen YL, Yuan RH, Yang WC, Hsu HC, Jeng YM. The stem cell E3-ligase Lin-41 promotes liver cancer progression through inhibition of microRNA-mediated gene silencing. J. Pathol 2013;229(3):486–96, http://dx.doi.org/10.1002/path.4130. [101] De Cecco L, Negri T, Brich S, Mauro V, Bozzi F, Dagrada G, Disciglio V, Sanfilippo R, Gronchi A, D’Incalci M, Casali PG, Canevari S, Pierotti MA, Pilotti S. Identification of a gene expression driven progression pathway in myxoid liposarcoma. Oncotarget 2014;5(15):5965–77. [102] Chang HM, Martinez NJ, Thornton JE, Hagan JP, Nguyen KD, Gregory RI. Trim71 cooperates with microRNAs to repress Cdkn1a expression and promote embryonic stem cell proliferation. Nat. Commun 2012;3:923. [103] Rybak A, Fuchs H, Hadian K, Smirnova L, Wulczyn EA, Michel G, Nitsch R, Krappmann D, Wulczyn FG. The let-7 target gene mouse lin-41 is a stem cell specific E3 ubiquitin ligase for the miRNA pathway protein Ago2. Nat. Cell Biol 2009;11(12):1411–20, http://dx.doi.org/10.1038/ncb1987. [104] Lee SH, Cho S, Sun Kim M, Choi K, Cho JY, Gwak HS, Kim YJ, Yoo H, Lee SH, Park JB, Kim JH. The ubiquitin ligase human TRIM71 regulates let-7 microRNA biogenesis via modulation of Lin28B protein. Biochim. Biophys. Acta 2014;1839(5):374–86, http://dx.doi.org/10.1016/j.bbagrm.2014.02.017. [105] Worringer KA, Rand TA, Hayashi Y, Sami S, Takahashi K, Tanabe K, Narita M, Srivastava D, Yamanaka S. The let-7/LIN-41 pathway regulates reprogramming to human induced pluripotent stem cells by controlling expression of prodifferentiation genes. Cell Stem Cell 2014;14(1):40–52, http://dx.doi.org/10.1016/j.stem.2013.11.001. [106] Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 2006;126(4):663–76. [107] Cano F, Bye H, Duncan LM, Buchet-Poyau K, Billaud M, Wills MR, Lehner PJ. The RNA-binding E3 ubiquitin ligase MEX-3C links ubiquitination with MHC-I mRNA degradation. EMBO J 2012;31(17):3596–606, http://dx.doi.org/10.1038/emboj.2012.218.