Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments.
Cancer Mutations of the Tumor Suppressor SPOP Disrupt the Formation of Active, Phase-Separated Compartments.
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肿瘤抑制剂的癌症突变破坏了活跃的，分离的隔室的形成。
DOI：
10.1016/j.molcel.2018.08.027
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发表时间：
2018-10-04
期刊：
影响因子：
16
通讯作者：
Mittag T
中科院分区：
文献类型：
--
作者：
Bouchard JJ;Otero JH;Scott DC;Szulc E;Martin EW;Sabri N;Granata D;Marzahn MR;Lindorff-Larsen K;Salvatella X;Schulman BA;Mittag T
肿瘤抑制基因SPOP(斑点状POZ蛋白)的突变会导致前列腺癌、乳腺癌和其他实体肿瘤。SPOP是cullin3-环泛素连接酶的底物接头，定位于核斑点。尽管SPOP中的癌症相关突变干扰了底物对连接酶的募集，但SPOP与其底物在液体核体中组装的机制以及SPOP突变对组装的影响尚不清楚。在这里，我们发现底物在体外触发SPOP的相分离，并在细胞中的无膜细胞器中共定位。酶活性与细胞共定位和体外中尺度组装的形成相关。疾病相关的SPOP突变导致原癌蛋白的积累干扰了无膜细胞器中的相分离和共定位，这表明底物导向的E3连接酶的相分离是泛素依赖的蛋白平衡调节的基础。众所周知，肿瘤抑制基因SPOP的突变会导致实体瘤。Bouchard和Otero等人。结果表明，在体外，SPOP相与底物分离；相同的相互作用在细胞中的无膜细胞器中共同定位。SPOP癌症突变扰乱了液-液分离，而液-液分离与功能丧失有关。
Mutations in the tumor suppressor SPOP (Speckle-type POZ protein) cause prostate, breast and other solid tumors. SPOP is a substrate adaptor of the cullin3-RING ubiquitin ligase and localizes to nuclear speckles. Although cancer-associated mutations in SPOP interfere with substrate recruitment to the ligase, mechanisms underlying assembly of SPOP with its substrates in liquid nuclear bodies, and effects of SPOP mutations on assembly are poorly understood. Here we show that substrates trigger phase separation of SPOP in vitro and co-localization in membraneless organelles in cells. Enzymatic activity correlates with cellular co-localization and in vitro mesoscale assembly formation. Diseaseassociated SPOP mutations that lead to the accumulation of proto-oncogenic proteins interfere with phase separation and co-localization in membraneless organelles, suggesting that substrate-directed phase separation of this E3 ligase underlies the regulation of ubiquitin-dependent proteostasis. Mutations in the tumor suppressor SPOP are known to cause solid tumors. Bouchard and Otero et al. show that SPOP phase separates with substrates in vitro; the same interactions mediate colocalization in membraneless organelles in cells. SPOP cancer mutations disrupt liquid-liquid phase separation, which correlates with loss of function.
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