TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase
TRIM37 defective in mulibrey nanism is a novel RING finger ubiquitin E3 ligase
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DOI：
10.1016/j.yexcr.2005.04.001
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发表时间：
2005-08-01
影响因子：
3.7
通讯作者：
Lehesjoki, AE
中科院分区：
文献类型：
--
作者：
Kallijärvi, J;Lahtinen, U;Lehesjoki, AE
多胎综合征是一种常染色体隐性遗传性产前发育性疾病，以畸形、心肌病和肝肿大为特征。编码三部分基序(Trim，环-B-盒-螺旋线圈)家族蛋白的TRIM37突变是多倍体纳米效应的基础。我们通过分析TRIM37的自素化来研究其环区泛素连接酶的活性。当与泛素共表达时，全长TRIM37及其TRIM结构域高度泛素化。在环状结构域中断的突变蛋白(Cys35Ser；Cys36Ser)和Leu76Pro突变蛋白中，多泛素化减少，Leu76Pro突变蛋白是一种影响TRIM37 TRIM结构域的疾病相关错义突变。细菌产生的GST-TRIM结构域融合蛋白，但不是它的Cys35Ser；Cys36Ser或Leu76Pro突变体在无细胞条件下被多泛素化，这意味着环依赖的修饰。在酵母双杂交筛选中，泛素也被确定为TRIM37的相互作用伙伴。异位表达的TRIM37在免疫荧光分析中迅速形成泛素、蛋白酶体亚单位和伴侣阳性的聚集体，将它们定义为侵袭体。Cys35Ser；Cys36Ser突变蛋白和Leu76Pro和Gly322Val患者突变蛋白明显不容易聚集，这意味着侵袭性靶向反映了TRIM37的一种生理功能。这些发现表明，TRIM37作为TRIM结构域依赖的E3泛素连接酶，暗示在多发性多发性硬化症的发病机制中，一种尚未确定的靶蛋白存在缺陷的泛素依赖降解。(C)2005 Elsevier Inc.保留所有权利。
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.