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The Journal of Cell Biology Jul 2021Centrosomes are composed of a centriolar core surrounded by pericentriolar material that nucleates microtubules. The ubiquitin ligase TRIM37 localizes to centrosomes,...
Centrosomes are composed of a centriolar core surrounded by pericentriolar material that nucleates microtubules. The ubiquitin ligase TRIM37 localizes to centrosomes, but its centrosomal roles are not yet defined. We show that TRIM37 does not control centriole duplication, structure, or the ability of centrioles to form cilia but instead prevents assembly of an ectopic centrobin-scaffolded structured condensate that forms by budding off of centrosomes. In ∼25% of TRIM37-deficient cells, the condensate organizes an ectopic spindle pole, recruiting other centrosomal proteins and acquiring microtubule nucleation capacity during mitotic entry. Ectopic spindle pole-associated transient multipolarity and multipolar segregation in TRIM37-deficient cells are suppressed by removing centrobin, which interacts with and is ubiquitinated by TRIM37. Thus, TRIM37 ensures accurate chromosome segregation by preventing the formation of centrobin-scaffolded condensates that organize ectopic spindle poles. Mutations in TRIM37 cause the disorder mulibrey nanism, and patient-derived cells harbor centrobin condensate-organized ectopic poles, leading us to propose that chromosome missegregation is a pathological mechanism in this disorder.
Topics: Cell Cycle Proteins; Centrioles; Centrosome; Chromosome Segregation; Humans; Microtubules; Mitosis; Mutation; Spindle Apparatus; Spindle Poles; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 33983387
DOI: 10.1083/jcb.202010180 -
ELife Jan 2021TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture...
TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule-organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity.
Topics: Cell Cycle Proteins; Cell Line; Centrioles; HeLa Cells; Humans; Microtubule-Organizing Center; Mulibrey Nanism; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 33491649
DOI: 10.7554/eLife.62640 -
Frontiers in Immunology 2020Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the () gene, encoding for TRIM37 a member of the TRIM E3...
Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the () gene, encoding for TRIM37 a member of the TRIM E3 ubiquitin ligase protein family. MUL patients are characterized by growth retardation, dysmorphic features, and a wide range of abnormalities affecting different organs. However, T-cell abnormalities have not been observed in MUL subjects, to date. Here we described the immunological features of a MUL child carrying recently identified mutations, a 17q22 deletion of maternal origin combined with a variant of paternal origin. Here we found quantitative and functional defects in CD4 T cells from this MUL case. Low levels of TRIM37 protein were specifically detected in CD4 T cells of MUL patient and associated with their altered proliferation and cytokine production. Of note, both CD4 and CD8 T lymphocytes of MUL child displayed an effector memory phenotype compared with healthy children. This clinical case research highlighted the possible role of TRIM37 in the control of immune cell number and function, especially in CD4 T cells. Finally, this study may contribute to the novel mechanistic studies aim of identifying, in depth, the role of the TRIM37 protein in the immune system.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Proliferation; Cells, Cultured; Child; Cytokines; Genetic Predisposition to Disease; Heredity; Humans; Immunologic Memory; Lymphocyte Activation; Male; Mulibrey Nanism; Mutation; Pedigree; Phenotype; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 33042106
DOI: 10.3389/fimmu.2020.01742 -
Bone Aug 2020Multiple molecular disorders can affect mechanisms regulating proliferation and differentiation of growth plate chondrocytes. Mutations in the TRIM37 gene cause the...
Multiple molecular disorders can affect mechanisms regulating proliferation and differentiation of growth plate chondrocytes. Mutations in the TRIM37 gene cause the Mulibrey nanism, a heritable growth disorder. Since chondrocytes are instrumental in long bone growth that is deficient in nanism, we hypothesized that TRIM37 defect could contribute to dysregulation of the chondrocyte cell cycle. Western blotting, confocal microscopy and imaging flow cytometry determined TRIM37 expression in CHON-002 cell lineage. We showed that TRIM37 is expressed during mitosis of chondrocytes and directly impacted their proliferation. During the chondrocyte cell cycle, TRIM37 was present in both nucleus and cytoplasm. During M phase we observed an increase of the TRIM37-Tubulin co-localization in comparison with G1, S and G2 phases. TRIM37 knock down inhibited proliferation, together with cell cycle anomalies and increased autophagy, while overexpression accordingly enhanced cell proliferation. We demonstrated that microRNA-223 directly targets TRIM37, and suggest that miR-223 regulates TRIM37 gene expression during the cell cycle. In summary, our results give clues to explain why TRIM37 deficiency in chondrocytes impacts bone growth. Modulating TRIM37 using miR-223 could be an approach to increase chondrogenesis.
Topics: Cell Line; Chondrocytes; MicroRNAs; Mitosis; Nuclear Proteins; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 32353567
DOI: 10.1016/j.bone.2020.115393 -
Pediatric Pulmonology Jan 2020Mulibrey nanism (MUL) is a rare growth restriction disorder with multiple organ manifestations caused by genetic defects affecting the TRIM37 protein. A perimyocardial...
BACKGROUND
Mulibrey nanism (MUL) is a rare growth restriction disorder with multiple organ manifestations caused by genetic defects affecting the TRIM37 protein. A perimyocardial heart disease is the most serious manifestation. Many MUL children appear to suffer from airway obstruction related to infection or exercise, prompting use of inhaled therapies. Asthma medication is continued up to adolescence or even to adulthood due to persisting of symptoms. The pulmonary pathophysiology has previously not been evaluated in any MUL cohort.
METHODS
Thirty three finnish MUL patients (median age 20 years) were investigated with several lung function tests: spirometry with bronchodilatation test, single-breath diffusing capacity for carbon monoxide, single-breath lung volume measurements with helium dilution, and thoracic gas volume, airway resistance and specific conductance measurements with a body plethysmograph. As MUL typically affects body proportions, all variables were compared with reference values and with predicted values calculated from sitting height.
RESULTS
Total lung capacity and forced vital capacity were markedly reduced (total lung capacity [TLC] and forced vital capacity [FVC], P < .001, 51%-63% of predicted) and also forced expiratory volume in the first second was reduced (FEV1; P < .001, 47%-57%). No signs of airway obstruction was seen (normal FEV1/FVC and specific airway conductance SGaw). Diffusing capacity (DLCO) was decreased (P < .001, 60%-67%) but when related to alveolar volume it was increased (DLCO/VA, P < .001, 130%-148%). Bronchodilatation suggesting active asthma (FEV1 change ≥12% and ≥200 mL) was found only in one patient.
CONCLUSION
MUL patients typically have volume restriction of the lungs, but function of the pulmonary tissue remains intact. Evidence of asthma in lung function testing at adult age is rare.
Topics: Adolescent; Adult; Asthma; Female; Humans; Lung; Male; Middle Aged; Mulibrey Nanism; Respiratory Function Tests; Total Lung Capacity; Young Adult
PubMed: 31502399
DOI: 10.1002/ppul.24518 -
The Annals of Thoracic Surgery Feb 2020Mulibrey nanism syndrome is a rare genetic disorder affecting multiple organ systems. The cardiovascular system is one of the most significantly affected, with...
Mulibrey nanism syndrome is a rare genetic disorder affecting multiple organ systems. The cardiovascular system is one of the most significantly affected, with simultaneous myocardial and pericardial disease. These patients are usually managed by pericardiectomy to resolve the milieu of hemodynamic problems ensuing due to concurrent constrictive and restrictive pathologies. We highlight the use of cardiac transplantation as a definitive management for a hemodynamically decompensated patient with Mulibrey nanism syndrome.
Topics: Echocardiography; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Male; Mulibrey Nanism; Tomography, X-Ray Computed; Young Adult
PubMed: 31260650
DOI: 10.1016/j.athoracsur.2019.05.021 -
International Journal of Molecular... Dec 2018TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review,... (Review)
Review
TRIpartite motif (TRIM) proteins are part of the largest subfamilies of E3 ligases that mediate the transfer of ubiquitin to substrate target proteins. In this review, we focus on TRIM37 in the normal cell and in pathological conditions, with an emphasis on the MULIBREY (MUscle-LIver-BRain-EYe) genetic disorder caused by mutations. TRIM37 is characterized by the presence of a RING domain, B-box motifs, and a coiled-coil region, and its C-terminal part includes the MATH domain specific to TRIM37. MULIBREY nanism is a rare autosomal recessive caused by mutations and characterized by severe pre- and postnatal growth failure. Constrictive pericarditis is the most serious anomaly of the disease and is present in about 20% of patients. The patients have a deregulation of glucose and lipid metabolism, including type 2 diabetes, fatty liver, and hypertension. Puzzlingly, MULIBREY patients, deficient for TRIM37, are plagued with numerous tumors. Among non-MULIBREY patients affected by cancer, a wide variety of cancers are associated with an overexpression of TRIM37. This suggests that normal cells need an optimal equilibrium in TRIM37 expression. Finding a way to keep that balance could lead to potential innovative drugs for MULIBREY nanism, including heart condition and carcinogenesis treatment.
Topics: Cardiovascular Diseases; Humans; Immunity, Innate; Inflammation; Mulibrey Nanism; NF-kappa B; Neoplasms; Nuclear Proteins; Polymorphism, Genetic; Tripartite Motif Proteins; Ubiquitin; Ubiquitin-Protein Ligases
PubMed: 30586926
DOI: 10.3390/ijms20010067 -
Autophagy 2018TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis,...
UNLABELLED
TRIM37 gene mutations cause mulibrey (muscle-liver-brain-eye) nanism, a severe growth disorder with prenatal onset. Although TRIM37 depletion normally induces apoptosis, patients with TRIM37 mutations have a high risk of developing tumors, suggesting that there may be an alternative pro-survival mechanism for TRIM37-deficient tumor cells. We find that TRIM37 interacts with MTOR and RRAGB proteins, enhances the MTOR-RRAGB interaction and promotes lysosomal localization of MTOR, thereby activating amino acid-stimulated MTORC1 signaling. In response to loss of TRIM37 functions, phosphorylation of TFEB is significantly reduced, resulting in its translocation into the nucleus enabling its transcriptional activation of genes involved in lysosome biogenesis and macroautophagy/autophagy. The enhanced autophagy depends on the inhibition of MTORC1 signaling and may serve as an alternative mechanism to survive the loss of TRIM37 functions. Our study unveils a positive role of TRIM37 in regulating the MTORC1-TFEB axis and provides mechanistic insights into the pathogenesis of mulibrey nanism, as well as potential therapeutic treatment.
ABBREVIATIONS
ACTB: actin beta; ATG: autophagy related; CASP3: caspase3; CLEAR: coordinated lysosomal expression and regulation; CQ: chloroquine; CTS: cathepsin proteases; CTSL: cathepsin L; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; LAMP1: lysosomal associated membrane protein 1; LAMP2: lysosomal associated membrane protein 2; LMNB1: lamin B1; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: MTOR complex 1; mulibrey: muscle-liver-brain-eye; NAC: N-acetyl-L-cysteine; PARP1: poly(ADP-ribose) polymerase 1; RAP2A: member of RAS oncogene family; RHEB: Ras homolog enriched in brain; ROS: reactive oxygen species; RPS6KB1: ribosomal protein S6 kinase B1; RRAGB: Ras related GTP binding B; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TRIM37: tripartite motif containing 37.
Topics: Amino Acids; Autophagy; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Cell Nucleus; Cell Survival; HEK293 Cells; Hep G2 Cells; Humans; Lysosomes; Mechanistic Target of Rapamycin Complex 1; Monomeric GTP-Binding Proteins; Nuclear Proteins; Phosphorylation; Protein Binding; Protein Transport; Signal Transduction; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 29940807
DOI: 10.1080/15548627.2018.1463120 -
Human Reproduction (Oxford, England) Jul 2018What is the timing of onset and clinical course of premature ovarian insufficiency (POI) in patients with Mulibrey nanism (MUL), a monogenic disorder caused by mutations...
STUDY QUESTION
What is the timing of onset and clinical course of premature ovarian insufficiency (POI) in patients with Mulibrey nanism (MUL), a monogenic disorder caused by mutations of the peroxisomal TRIM37 gene?
SUMMARY ANSWER
The number of ovarian follicles is highly reduced already in infant and young MUL girls and the majority of them will have early depletion of follicles resulting in clinical and biochemical signs of POI.
WHAT IS KNOWN ALREADY
Both female and male patients with MUL show failure of sexual maturation, signs of hypogonadism and infertility.
STUDY DESIGN, SIZE, DURATION
We studied the gonadal function, pubertal development and ovarian reserve in 33 MUL patients aged 5.1-47.3 years (median age 22.3) at the end of observation. The patients were followed between 2004 and 2014 and 19 pubertal or postpubertal patients were enrolled in a cross-sectional study.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The period of postnatal activation of the hypothalamic-pituitary-gonadal axis (minipuberty), pubertal development and menstrual history were assessed longitudinally. The cross-sectional study included gynecological examination, analysis of reproductive hormones and ultrasonography with evaluation of ovarian volume and antral follicle count.
MAIN RESULTS AND THE ROLE OF CHANCE
Infant girls experienced a transient minipuberty with a high FSH surge. In childhood, gonadotropins were normal or slightly elevated but began to rise to hypergonadotropic levels in prepuberty. Anti-Müllerian hormone (AMH) levels remained undetectable or low throughout childhood. The onset of puberty occurred spontaneously and the median age at menarche was 12.5 years. Of the patients, 54% never attained regular menses and 10 years from menarche, only 8% of the women menstruated regularly. In the cross-sectional study, none of the patients had normal ovarian morphology under ultrasonography. Ovaries were hypoplastic and 82% had no or fewer than two visible antral follicles. AMH levels were undetectable in the vast majority (89%).
LIMITATIONS, REASONS FOR CAUTION
The Finnish MUL patients genotypically form a homogenous group and therefore it is possible, that different TRIM37 mutations lead to different hypogonadal phenotypes. However, to date there is no known genotype-phenotype correlation in MUL.
WIDER IMPLICATIONS OF THE FINDINGS
In MUL, AMH is a useful marker of ovarian function. MUL should be added to the list of syndromes associated with POI and correspondingly, TRIM37 should be added to the list of genes associated with POI. To our knowledge, TRIM37 is the first known gene coding for a peroxisomal membrane protein associated with female gonadal failure and infertility. Elucidating the role of syndromic genes in reproduction may aid in a greater understanding of ovarian biology.
STUDY FUNDING/COMPETING INTEREST(S)
This study was supported by the Finnish Foundation for Pediatric Research, Finska Läkaresällskapet, the Sigrid Jusélius Foundation and Helsinki University Hospital Research Funds. The authors declare no conflicts of interest.
TRIAL REGISTRATION NUMBER
Not applicable.
Topics: Adolescent; Adult; Anti-Mullerian Hormone; Child; Child, Preschool; Female; Humans; Hypothalamo-Hypophyseal System; Middle Aged; Mulibrey Nanism; Ovarian Reserve; Ovary; Primary Ovarian Insufficiency; Young Adult
PubMed: 29860321
DOI: 10.1093/humrep/dey103 -
The Canadian Journal of Cardiology May 2018Patients with Mulibrey nanism (MUL) present with growth failure and multiple organ manifestations, and MUL is caused by mutations in TRIM37. In this article, we report...
Patients with Mulibrey nanism (MUL) present with growth failure and multiple organ manifestations, and MUL is caused by mutations in TRIM37. In this article, we report on the first case series of Japanese patients with MUL who developed congestive heart failure due to constrictive pericarditis. Our case series suggests that early diagnosis and total pericardiectomy before adherence of the pericardium might provide clinical benefit and better prognosis for MUL.
Topics: Child; Child, Preschool; Early Diagnosis; Echocardiography; Female; Genetic Testing; Heart Failure; Humans; Magnetic Resonance Imaging, Cine; Mulibrey Nanism; Mutation; Nuclear Proteins; Pericardiectomy; Pericarditis, Constrictive; Pericardium; Prognosis; Treatment Outcome; Tripartite Motif Proteins; Ubiquitin-Protein Ligases
PubMed: 29731032
DOI: 10.1016/j.cjca.2018.02.008