Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Cancer Institute, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China.
Signal Transduct Target Ther. 2020 Apr 24;5(1):42. doi: 10.1038/s41392-020-0140-z.
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 ubiquitin ligase controls TNFAIP1 degradation to regulate cancer cell migration.
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，包括肿瘤发生和癌细胞迁移。然而，TNFAIP1 降解的调节机制在很大程度上仍未被揭示。在本研究中，我们采用无标记定量蛋白质组学方法，鉴定出 TNFAIP1 是 Cullin-RING E3 泛素连接酶（CRL）复合物的一种新型泛素靶标。更重要的是，鉴定出 Cul3-ROC1（CRL3），即 CRL 亚家族，能够特异性地与 TNFAIP1 相互作用，并促进其多泛素化和降解。在机制上，BTBD9，CRL3 复合物的一个特定衔接子组件，被进一步定义为在细胞中结合并促进 TNFAIP1 的泛素化和降解。因此，BTBD9 的下调通过上调 TNFAIP1 的表达促进了肺癌细胞的迁移，而 TNFAIP1 的缺失则消除了这种效应。最后，生物信息学和临床样本分析显示，BTBD9 在人肺癌中下调而 TNFAIP1 过表达，这与患者的总体生存不良相关。总之，这些发现揭示了 CRL3 泛素连接酶控制 TNFAIP1 降解以调节癌细胞迁移的一个先前未被认识的机制。
