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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 -
The Journal of Cell Biology Sep 2017Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal...
Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal human peroxisomal biogenesis disorders (PBDs). gene mutations cause muscle-liver-brain-eye (mulibrey) nanism. We found that TRIM37 localizes in peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with its C-terminal 51 amino acids (CT51), which is required for PTS protein import. PEX5 mutations (K464A or ΔCT51), or TRIM37 depletion or mutation, reduce PEX5 abundance by promoting its proteasomal degradation, thereby impairing its functions in cargo binding and PTS protein import in human cells. TRIM37 or PEX5 depletion induces apoptosis and enhances sensitivity to oxidative stress, underscoring the cellular requirement for functional peroxisomes. Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD.
Topics: Animals; Apoptosis; Genetic Predisposition to Disease; HEK293 Cells; Hep G2 Cells; Humans; Mice; Mulibrey Nanism; Mutation; Nuclear Proteins; Organelle Biogenesis; Oxidative Stress; Peroxisome-Targeting Signal 1 Receptor; Peroxisomes; Phenotype; Proteasome Endopeptidase Complex; Protein Binding; Protein Interaction Domains and Motifs; Protein Stability; Protein Transport; Proteolysis; RAW 264.7 Cells; Receptors, Cytoplasmic and Nuclear; Time Factors; Transfection; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Ubiquitination
PubMed: 28724525
DOI: 10.1083/jcb.201611170 -
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 -
Ultrasound in Obstetrics & Gynecology :... Apr 2004
Topics: Adult; Ascites; Dwarfism; Electrocardiography; Female; Fetal Diseases; Fetal Growth Retardation; Heart Diseases; Humans; Magnetic Resonance Imaging; Pregnancy
PubMed: 15065196
DOI: 10.1002/uog.1024 -
The Journal of Biological Chemistry Jun 2001We have identified three new tumor necrosis factor-receptor associated factor (TRAF) domain-containing proteins in humans using bioinformatics approaches, including:...
We have identified three new tumor necrosis factor-receptor associated factor (TRAF) domain-containing proteins in humans using bioinformatics approaches, including: MUL, the product of the causative gene in Mulibrey Nanism syndrome; USP7 (HAUSP), an ubiquitin protease; and SPOP, a POZ domain-containing protein. Unlike classical TRAF family proteins involved in TNF family receptor (TNFR) signaling, the TRAF domains (TDs) of MUL, USP7, and SPOP are located near the NH(2) termini or central region of these proteins, rather than carboxyl end. MUL and USP7 are capable of binding in vitro via their TDs to all of the previously identified TRAF family proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, and TRAF6), whereas the TD of SPOP interacts weakly with TRAF1 and TRAF6 only. The TD of MUL also interacted with itself, whereas the TDs of USP7 and SPOP did not self-associate. Analysis of various MUL and USP7 mutants by transient transfection assays indicated that the TDs of these proteins are necessary and sufficient for suppressing NF-kappaB induction by TRAF2 and TRAF6 as well as certain TRAF-binding TNF family receptors. In contrast, the TD of SPOP did not inhibit NF-kappaB induction. Immunofluorescence confocal microscopy indicated that MUL localizes to cytosolic bodies, with targeting to these structures mediated by a RBCC tripartite domain within the MUL protein. USP7 localized predominantly to the nucleus, in a TD-dependent manner. Data base searches revealed multiple proteins containing TDs homologous to those found in MUL, USP7, and SPOP throughout eukaryotes, including yeast, protists, plants, invertebrates, and mammals, suggesting that this branch of the TD family arose from an ancient gene. We propose the moniker TEFs (TD-encompassing factors) for this large family of proteins.
Topics: Amino Acid Sequence; Animals; Computational Biology; Cytosol; Endopeptidases; Evolution, Molecular; Humans; Jurkat Cells; Molecular Sequence Data; NF-kappa B; Nuclear Proteins; Phylogeny; Protein Structure, Tertiary; Proteins; Receptors, Tumor Necrosis Factor; Repressor Proteins; Sequence Homology, Amino Acid; TNF Receptor-Associated Factor 1; Tripartite Motif Proteins; Ubiquitin Thiolesterase; Ubiquitin-Protein Ligases; Ubiquitin-Specific Peptidase 7
PubMed: 11279055
DOI: 10.1074/jbc.M100354200 -
Kardiologia Polska 2016
Topics: Adult; Female; Heart Failure; Humans; Liver Failure; Mulibrey Nanism; Ovarian Neoplasms; Pericardiectomy; Pericarditis, Constrictive; Young Adult
PubMed: 27150563
DOI: 10.5603/KP.2016.0021 -
Mechanisms of Development Oct 2001We studied the expression of MUL, a gene encoding a novel member of the RING-B-Box-Coiled Coil family of zinc finger proteins that underlies the human inherited...
We studied the expression of MUL, a gene encoding a novel member of the RING-B-Box-Coiled Coil family of zinc finger proteins that underlies the human inherited disorder, Mulibrey nanism. In early human and mouse embryogenesis MUL is expressed in dorsal root and trigeminal ganglia, liver and in epithelia of multiple tissues.
Topics: Animals; Dwarfism; Epithelium; Ganglia, Spinal; Gene Expression Regulation, Developmental; Humans; In Situ Hybridization; Liver; Mice; Nuclear Proteins; Trigeminal Ganglion; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Zinc Fingers
PubMed: 11578880
DOI: 10.1016/s0925-4773(01)00491-9