title: TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase.
abstract: Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder characterized by dysmorphic features, cardiomyopathy, and hepatomegaly. Mutations in TRIM37 encoding a tripartite motif (TRIM, RING-B-box-coiled-coil)-family protein underlie mulibrey nanism. We investigated the ubiquitin ligase activity predicted for the RING domain of TRIM37 by analyzing its autoubiquitination. Full-length TRIM37 and its TRIM domain were highly polyubiquitinated when co-expressed with ubiquitin. Polyubiquitination was decreased in a mutant protein with disrupted RING domain (Cys35Ser;Cys36Ser) and in the Leu76Pro mutant protein, a disease-associated missense mutation affecting the TRIM domain of TRIM37. Bacterially produced GST-TRIM domain fusion protein, but not its Cys35Ser;Cys36Ser or Leu76Pro mutants, were polyubiquitinated in cell-free conditions, implying RING-dependent modification. Ubiquitin was also identified as an interaction partner for TRIM37 in a yeast two-hybrid screen. Ectopically expressed TRIM37 rapidly formed aggregates that were ubiquitin-, proteasome subunit-, and chaperone-positive in immunofluorescence analysis, defining them as aggresomes. The Cys35Ser;Cys36Ser mutant and the Leu76Pro and Gly322Val patient mutant proteins were markedly less prone to aggregation, implying that aggresomal targeting reflects a physiological function of TRIM37. These findings suggest that TRIM37 acts as a TRIM domain-dependent E3 ubiquitin ligase and imply defective ubiquitin-dependent degradation of an as-yet-unidentified target protein in the pathogenesis of mulibrey nanism.
authors.affiliation: Folkhälsan Institute of Genetics, Department of Medical Genetics and Neuroscience Center, Biomedicum Helsinki, 00014 University of Helsinki, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Kallijärvi
authors.forename: Ulla
authors.initials: U
authors.lastname: Lahtinen
authors.forename: Riikka
authors.initials: R
authors.lastname: Hämäläinen
authors.forename: Marita
authors.initials: M
authors.lastname: Lipsanen-Nyman
authors.forename: Jorma J
authors.initials: JJ
authors.lastname: Palvimo
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
mesh_terms: D000483:Alleles; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004392:Dwarfism / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D009687:Nuclear Proteins / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D012995:Solubility; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism; D016335:Zinc Fingers / Q000235:genetics*
chemical_list: D046911:Macromolecular Substances; D009687:Nuclear Proteins; D000070584:Tripartite Motif Proteins; D025801:Ubiquitin; C411745:TRIM37 protein, human; D044767:Ubiquitin-Protein Ligases