The CRL3BTBD9 E3 ubiquitin ligase complex targets TNFAIP1 for degradation to suppress cancer cell migration
The CRL3BTBD9 E3 ubiquitin ligase complex targets TNFAIP1 for degradation to suppress cancer cell migration
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CRL3(BTBD9) E3 泛素连接酶复合物靶向 TNFAIP1 进行降解，从而抑制癌细胞迁移
DOI：
10.1038/s41392-020-0140-z
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发表时间：
2020-04-24
影响因子：
39.3
通讯作者：
Jia, Lijun
中科院分区：
文献类型：
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作者：
Li, Lihui;Zhang, Wenjuan;Jia, Lijun
肿瘤坏死因子α诱导蛋白1(TNFAIP1)调节多种重要的生物学过程，包括肿瘤的发生和癌细胞的迁移。然而，TNFAIP1降解的调节机制在很大程度上仍然难以捉摸。在本研究中，利用无标记定量蛋白质组学方法，TNFAIP1被鉴定为库林环E3泛素连接酶(CRL)复合体的一个新的泛素靶点。更重要的是，CUL3-ROC1(CRL3)是CRLS的一个亚家族，被发现与TNFAIP1特异性地相互作用，促进其多泛素化和降解。在机制上，进一步定义了CRL3复合体的特异适配子成分BTBD9，以结合和促进细胞内TNFAIP1的泛素化和降解。因此，BTBD9的下调通过上调TNFAIP1的表达来促进肺癌细胞的迁移，而TNFAIP1的缺失则取消了这一作用。最后，生物信息学和临床样本分析表明，BTBD9在人类肺癌中下调，而TNFAIP1过表达，这与患者总体生存率较低有关。综上所述，这些发现揭示了之前未知的CRL3(BTBD9)泛素连接酶控制TNFAIP1降解以调节癌细胞迁移的机制。
Tumor necrosis factor alpha-induced protein 1 (TNFAIP1) modulates a plethora of important biological processes, including tumorigenesis and cancer cell migration. However, the regulatory mechanism of TNFAIP1 degradation remains largely elusive. In the present study, with a label-free quantitative proteomic approach, TNFAIP1 was identified as a novel ubiquitin target of the Cullin-RING E3 ubiquitin ligase (CRL) complex. More importantly, Cul3-ROC1 (CRL3), a subfamily of CRLs, was identified to specifically interact with TNFAIP1 and promote its polyubiquitination and degradation. Mechanistically, BTBD9, a specific adaptor component of CRL3 complex, was further defined to bind and promote the ubiquitination and degradation of TNFAIP1 in cells. As such, downregulation of BTBD9 promoted lung cancer cell migration by upregulating the expression of TNFAIP1, whereas TNFAIP1 deletion abrogated this effect. Finally, bioinformatics and clinical sample analyses revealed that BTBD9 was downregulated while TNFAIP1 was overexpressed in human lung cancer, which was associated with poor overall survival of patients. Taken together, these findings reveal a previously unrecognized mechanism by which the CRL3(BTBD9) ubiquitin ligase controls TNFAIP1 degradation to regulate cancer cell migration.