TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase

被引:66
作者
Kallijärvi, J
Lahtinen, U
Hämäläinen, R
Lipsanen-Nyman, M
Palvimo, JJ
Lehesjoki, AE [1 ]
机构
[1] Univ Helsinki, Biomedicum Helsinki, Folkhalsan Inst Genet, Dept Med Genet, FIN-00014 Helsinki, Finland
[2] Univ Helsinki, Cent Hosp, FIN-00014 Helsinki, Finland
[3] Univ Helsinki, Inst Biomed, FIN-00014 Helsinki, Finland
[4] Univ Kuopio, Dept Med Biochem, FIN-70211 Kuopio, Finland
基金
芬兰科学院;
关键词
mulibrey nanism; RING finger; TRIM domain; ubiquitin ligase; aggresome;
D O I
10.1016/j.yexcr.2005.04.001
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:146 / 155
页数:10
相关论文
共 35 条
[1]   Gene encoding a new RING-B-box-Coiled-coil protein is mutated in mulibrey nanism [J].
Avela, K ;
Lipsanen-Nyman, M ;
Idänheimo, N ;
Seemanová, E ;
Rosengren, S ;
Mäkelä, TP ;
Perheentupa, J ;
de la Chapelle, A ;
Lehesjoki, AE .
NATURE GENETICS, 2000, 25 (03) :298-301
[2]   Functional characterization of the Opitz syndrome gene product (midin): evidence for homodimerization and association with microtubules throughout the cell cycle [J].
Cainarca, S ;
Messali, S ;
Ballabio, A ;
Meroni, G .
HUMAN MOLECULAR GENETICS, 1999, 8 (08) :1387-1396
[3]   The Familial Mediterranean Fever protein interacts and colocalizes with a putative Golgi transporter [J].
Chen, XG ;
Bykhovskaya, Y ;
Tidow, N ;
Hamon, M ;
Bercovitz, Z ;
Spirina, O ;
Fischel-Ghodsian, N .
PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE, 2000, 224 (01) :32-40
[4]   New mutations in MID1 provide support for loss of function as the cause of X-linked Opitz syndrome [J].
Cox, TC ;
Allen, LR ;
Cox, LL ;
Hopwood, B ;
Goodwin, B ;
Haan, E ;
Suthers, GK .
HUMAN MOLECULAR GENETICS, 2000, 9 (17) :2553-2562
[5]  
CRANE DI, 1994, J BIOL CHEM, V269, P21835
[6]   A NOVEL GENETIC SYSTEM TO DETECT PROTEIN PROTEIN INTERACTIONS [J].
FIELDS, S ;
SONG, OK .
NATURE, 1989, 340 (6230) :245-246
[7]   Ubiquitination: RING for destruction? [J].
Freemont, PS .
CURRENT BIOLOGY, 2000, 10 (02) :R84-R87
[8]   Hassles with taking out the garbage: Aggravating aggresomes [J].
Garcia-Mata, R ;
Gao, YS ;
Sztul, E .
TRAFFIC, 2002, 3 (06) :388-396
[9]  
Hamalainen Riikka H, 2004, Hum Mutat, V23, P522, DOI 10.1002/humu.9233
[10]   PROPOSED ROLE OF ATP IN PROTEIN BREAKDOWN - CONJUGATION OF PROTEINS WITH MULTIPLE CHAINS OF THE POLYPEPTIDE OF ATP-DEPENDENT PROTEOLYSIS [J].
HERSHKO, A ;
CIECHANOVER, A ;
HELLER, H ;
HAAS, AL ;
ROSE, IA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (04) :1783-1786