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: Jukka Kallijärvi, Ulla Lahtinen, Riikka Hämäläinen, Marita Lipsanen-Nyman, Jorma J Palvimo, Anna-Elina Lehesjoki
• Journal: Experimental cell research (Exp Cell Res) Vol. 308 Issue 1 Pg. 146-55 (Aug 01 2005) ISSN: 0014-4827 [Print] United States
• PMID: 15885686 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Macromolecular Substances
• Nuclear Proteins
• Tripartite Motif Proteins
• Ubiquitin
• TRIM37 protein, human
• Ubiquitin-Protein Ligases

Topics

• Alleles
• Animals
• COS Cells
• Chlorocebus aethiops
• Dwarfism (genetics)
• Gene Expression Regulation
• Humans
• Macromolecular Substances (chemistry, metabolism)
• Mutagenesis, Site-Directed
• Mutation
• Nuclear Proteins (chemistry, genetics, metabolism)
• Solubility
• Tripartite Motif Proteins
• Ubiquitin (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Zinc Fingers (genetics)