212 research outputs found
TRIM32 ubiquitin E3 ligase, one enzyme for several pathologies: From muscular dystrophy to tumours
No full textTRIM32 is a member of the TRIpartite Motif family characterised by the presence of an N-terminal three-domain-module that includes a RING domain, which confers E3 ubiquitin ligase activity, one or two B-box domains and a Coiled-Coil region that mediates oligomerisation. Several TRIM32 substrates were identified including muscular proteins and proteins involved in cell cycle regulation and cell motility. As ubiquitination is a versatile post-translational modification that can affect target turnover, sub-cellular localisation or activity, it is likely that diverse substrates may be differentially affected by TRIM32-mediated ubiquitination, reflecting its multi-faceted roles in muscle physiology, cancer and immunity. With particular relevance for muscle physiology, mutations in TRIM32 are associated with autosomal recessive Limb-Girdle Muscular Dystrophy 2H, a muscle-wasting disease with variable clinical spectrum ranging from almost asymptomatic to wheelchair-bound patients. In this review, we will focus on the ability of TRIM32 to mark specific substrates for proteasomal degradation discussing how the TRIM32-proteasome axis may (i) be important for muscle homeostasis and for the pathogenesis of muscular dystrophy; and (ii) define either an oncogenic or tumour suppressive role for TRIM32 in the context of different types of cancer
Emerging Roles of the TRIM E3 Ubiquitin Ligases MID1 and MID2 in Cytokinesis
No full textUbiquitination is a post-translational modification that consists of ubiquitin attachment
to target proteins through sequential steps catalysed by activating (E1), conjugating
(E2), and ligase (E3) enzymes. Protein ubiquitination is crucial for the regulation of many
cellular processes not only by promoting proteasomal degradation of substrates but also
re-localisation of cellular factors and modulation of protein activity. Great importance
in orchestrating ubiquitination relies on E3 ligases as these proteins recognise the
substrate that needs to be modified at the right time and place. Here we focus
on two members of the TRIpartite Motif (TRIM) family of RING E3 ligases, MID1,
and MID2. We discuss the recent findings on these developmental disease-related
proteins analysing the link between their activity on essential factors and the regulation
of cytokinesis highlighting the possible consequence of alteration of this process in
pathological conditions
TRIM/RBCC, a novel class of 'single protein RING finger' E3 ubiquitin ligases
No full textThe TRIM/RBCC proteins are defined by the presence of the tripartite motif composed of a RING domain, one or two B-box motifs and a coiled-coil region. These proteins are involved in a plethora of cellular processes such as apoptosis, cell cycle regulation and viral response. Consistently, their alteration results in many diverse pathological conditions. The highly conserved modular structure of these proteins suggests that a common biochemical function may underlie their assorted cellular roles. Here, we review recent data indicating that some TRIM/RBCC proteins are implicated in ubiquitination and propose that this large protein family represents a novel class of 'single protein RING finger' ubiquitin E3 ligases
TRIM proteins legitimately enter the MAGEic RING
No full textComment on 'The melanoma-associated antigen 1 (MAGEA1) protein stimulates the E3 ubiquitin-ligase activity of TRIM31 within a TRIM31-MAGEA1-NSE4 complex' [Cell Cycle. 2015
MID1 mutations in patients with X-linked Opitz G/BBB syndrome
No full textMutations in the MID1 gene are responsible for the X-linked form of Opitz G/BBB syndrome (OS), a disorder that affects the development of midline structures. OS is characterized by hypertelorism, hypospadias, laryngo-tracheo-esophageal (LTE) abnormalities, and additional midline defects. Cardiac, anal, and neurological defects are also present. The expressivity of OS is highly variable, even within the same family. We reviewed all the MID1 mutations reported so far, in both familial and sporadic cases. The mutations are scattered along the entire length of the gene and consist of missense and nonsense mutations, insertions and deletions, either in-frame or causing frameshifts, and deletions of either single exons or the entire MID1 coding region. The variety of described mutations and the lack of a strict genotype-phenotype correlation confirm the previous suggestion of the OS phenotype being caused by a loss-of-function mechanism. However, although a specific mutation cannot entirely account for the observed phenotype, we observed preferential association between some types of mutation and specific clinical manifestations, e.g., brain anatomical defects and truncating mutations. This may suggest that the pathogenetic mechanism underlying the OS phenotype is more complex and may vary among the affected organs
The sulfatase gene family
No full textDuring the past few years, molecular analyses have provided important insights into the biochemistry and genetics of the sulfatase family of enzymes, identifying the molecular bases of inherited diseases caused by sulfatase deficiencies. New members of the sulfatase gene family have been identified in man and other species using a genomic approach. These include the gene encoding arylsulfatase E, which is involved in X-linked recessive chondrodysplasia punctata, a disorder of cartilage and bone development. Another important breakthrough has been the discovery of the biochemical basis of multiple sulfatase deficiency, an autosomal recessive disorder characterized by a severe of all sulfatase activities. These discoveries, together with the resolution of the crystallographic structure of sulfatases, have improved our understanding of the function and evolution of this fascinating family of enzymes
Microtubular TRIM36 E3 Ubiquitin Ligase in Embryonic Development and Spermatogenesis
No full textTRIM36 is a member of the tripartite motif (TRIM) family of RING-containing proteins, also known as Haprin, which was first discovered for its abundance in testis and found to be implicated in the spermatozoa acrosome reaction. TRIM36 is a microtubule-associated E3 ubiquitin ligase that plays a role in cytoskeletal organization, and according to data gathered in different species, coordinates growth speed and stability, acting on the microtubules’ plus end, and impacting on cell cycle progression. TRIM36 is also crucial for early developmental processes, in Xenopus, where it is needed for dorso-ventral axis formation, but also in humans as bi-allelic mutations in the TRIM36 gene cause a form of severe neural tube closure defect, called anencephaly. Here, we review TRIM36-related mechanisms implicated in such composite physiological and pathological processes
TRIMming p53’s anticancer activity
No full textSeveral TRIM proteins control abundance and activity of p53. Along this route, TRIM proteins have a serious impact on carcinogenesis and prognosis for cancer patients. In the past years, a significant increase has been made in our understanding of how the TRIM protein family controls p53 activity
TRIM family: Pleiotropy and diversification through homomultimer and heteromultimer formation
No full textThe TRIM family is composed of multidomain ubiquitin E3 ligases characterized by the presence of the N-terminal tripartite motif (RING, B-boxes, and coiled coil). TRIM proteins transfer the ubiquitin moiety to specific substrates but are also involved in ubiquitin-like modifications, in particular SUMOylation and ISGylation. The TRIM family members are involved in a plethora of biological and physiological processes and, when altered, are implicated in many pathological conditions. Growing evidence indicates the pleiotropic effect of several TRIM genes, each of which might be connected to very diverse cellular processes. As a way to reconcile a single family member with several functions, we propose that structural features, that is, their ability to homo- and hetero-di(multi)merize, can increase and diversify TRIM ubiquitin E3 ligase capability
Mig12, a novel Opitz syndrome gene product partner, is expressed in the embryonic ventral midline and co-operates with Mid1 to bundle and stabilize microtubules
No full textOpitz G/BBB syndrome is a genetic disorder characterized by developmental midline abnormalities, such as hypertelorism, cleft palate, and hypospadias. The gene responsible for the X-linked form of this disease, MID1, encodes a TRIM/RBCC protein that is anchored to the microtubules. The association of Mid1 with the cytoskeleton is regulated by dynamic phosphorylation, through the interaction with the alpha4 subunit of phosphatase 2A (PP2A). Mid1 acts as an E3 ubiquitin ligase, regulating PP2A degradation on microtubules.
In spite of these findings, the biological role exerted by the Opitz syndrome gene product is still unclear and the presence of other potential interacting moieties in the Mid1 structure prompted us to search for additional cellular partners. Through a yeast two-hybrid screening approach, we identified a novel gene, MIG12, whose protein product interacts with Mid1. We confirmed by immunoprecipitation that this interaction occurs in vivo and that it is mediated by the Mid1 coiled-coil domain. We found that Mig12 is mainly expressed in the neuroepithelial midline, urogenital apparatus, and digits during embryonic development. Transiently expressed Mig12 is found diffusely in both nucleus and cytoplasm, although it is enriched in the microtubule-organizing center region. Consistently with this, endogenous Mig12 protein is partially detected in the polymerized tubulin fraction after microtubule stabilization. When co-transfected with Mid1, Mig12 is massively recruited to thick filamentous structures composed of tubulin. These microtubule bundles are resistant to high doses of depolymerizing agents and are composed of acetylated tubulin, thus representing stabilized microtubule arrays.
Our findings suggest that Mig12 co-operates with Mid1 to stabilize microtubules. Mid1-Mig12 complexes might be implicated in cellular processes that require microtubule stabilization, such as cell division and migration. Impairment in Mig12/Mid1-mediated microtubule dynamic regulation, during the development of embryonic midline, may cause the pathological signs observed in Opitz syndrome patients
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