CRL3-SPOP ubiquitin ligase complex suppresses the growth of diffuse large B-cell lymphoma by negatively regulating the MyD88/NF-κB signaling
CRL3-SPOP ubiquitin ligase complex suppresses the growth of diffuse large B-cell lymphoma by negatively regulating the MyD88/NF-κB signaling
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CRL3-SPOP 泛素连接酶复合物通过负调节 MyD88/NF-kappa B 信号传导抑制弥漫性大 B 细胞淋巴瘤的生长
DOI：
10.1038/s41375-019-0661-z
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发表时间：
2020-05-01
期刊：
影响因子：
11.4
通讯作者：
Wang, Chenji
中科院分区：
文献类型：
--
作者：
Jin, Xiaofeng;Shi, Qing;Wang, Chenji
MyD 88的复发性致癌突变已在多种淋巴恶性肿瘤中被鉴定。MyD 88的功能获得性突变组成性激活下游NF-κ B信号通路，导致细胞增殖和存活增加。然而，MyD 88活性是否可以在MyD 88-野生型淋巴恶性肿瘤中异常调节仍然知之甚少。SPOP是基于CUL 3的E3泛素连接酶复合物的衔接蛋白，并且是前列腺癌和子宫内膜癌中频繁突变的基因。在这项研究中，我们发现，SPOP结合，并通过识别MyD 88中的非典型SPOP结合基序诱导MyD 88的非降解泛素化。这种修饰阻断Myddosome组装和下游NF-κ B活化。SPOP在淋巴系统恶性肿瘤的一个子集中发生突变，包括弥漫性大B细胞淋巴瘤（DLBCL）。类恶性肿瘤相关的SPOP突变体表现出与MyD 88结合受损和NF-κ B活化抑制。DLBCL相关的、SPOP结合缺陷的MyD 88突变体逃避了SPOP介导的泛素化，它们对NF-κ B活化的作用强于野生型MyD 88。此外，SPOP通过抑制MyD 88/NF-κ B信号传导抑制DLBCL细胞的体外生长和肿瘤异种移植物的体内生长。因此，SPOP在DLBCL中充当肿瘤抑制剂。SPOP-MyD 88结合界面的突变可能破坏SPOP-MyD 88调节轴，并促进异常的MyD 88/NF-κ B活化和DLCBL中的细胞生长。
Recurrent oncogenic mutations of MyD88 have been identified in a variety of lymphoid malignancies. Gain-of-function mutations of MyD88 constitutively activate downstream NF-kappa B signaling pathways, resulting in increased cellular proliferation and survival. However, whether MyD88 activity can be aberrantly regulated in MyD88-wild-type lymphoid malignancies remains poorly understood. SPOP is an adaptor protein of CUL3-based E3 ubiquitin ligase complex and frequently mutated genes in prostate and endometrial cancers. In this study, we reveal that SPOP binds to and induces the nondegradative ubiquitination of MyD88 by recognizing an atypical SPOP-binding motif in MyD88. This modification blocks Myddosome assembly and downstream NF-kappa B activation. SPOP is mutated in a subset of lymphoid malignancies, including diffuse large B-cell lymphoma (DLBCL). Lymphoid malignancies-associated SPOP mutants exhibited impaired binding to MyD88 and suppression of NF-kappa B activation. The DLBCL-associated, SPOP-binding defective mutants of MyD88 escaped from SPOP-mediated ubiquitination, and their effect on NF-kappa B activation is stronger than that of wild-type MyD88. Moreover, SPOP suppresses DLBCL cell growth in vitro and tumor xenograft in vivo by inhibiting the MyD88/NF-kappa B signaling. Therefore, SPOP acts as a tumor suppressor in DLBCL. Mutations in the SPOP-MyD88 binding interface may disrupt the SPOP-MyD88 regulatory axis and promote aberrant MyD88/NF-kappa B activation and cell growth in DLCBL.