IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling.
IMiDs induce FAM83F degradation via an interaction with CK1α to attenuate Wnt signalling.
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DOI：
10.26508/lsa.202000804
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发表时间：
2021-03
影响因子：
4.4
通讯作者：
Sapkota GP
中科院分区：
文献类型：
--
作者：
Dunbar K;Macartney TJ;Sapkota GP
IMiDs诱导FAM83F-CK1α复合物的降解，但没有其他FAM83-CK1α复合物的降解，导致Wnt信号的衰减。免疫调节亚胺药物（IMiDs）结合Cul4A E3连接酶复合物的底物受体CRBN，使新底物（如CK1α）募集，并通过泛素蛋白酶体系统降解。在这里，我们报告了FAM83F作为这样一个新底物。八个FAM83蛋白（A-H）相互作用并调节CK1α的亚细胞分布。我们证明了imid诱导的FAM83F降解需要与CK1α相关。然而，没有其他FAM83蛋白被IMiDs降解。我们最近发现FAM83F是典型Wnt信号通路的中介。imid诱导的FAM83F降解减弱了结直肠癌细胞中的Wnt信号，并从质膜上去除了CK1α，反映了FAM83F基因消融所观察到的表型。有趣的是，FAM83G的表达，也与CK1α结合，似乎减弱了imid诱导的CK1α降解，这表明FAM83G对CK1α具有保护作用。我们的研究结果表明，IMiDs降解靶蛋白的效率和程度取决于靶蛋白所在的固有多蛋白复合物的性质。
IMiDs induce the degradation of the FAM83F–CK1α complex but no other FAM83–CK1α complexes, resulting in attenuation of Wnt signalling. Immunomodulatory imide drugs (IMiDs) bind CRBN, a substrate receptor of the Cul4A E3 ligase complex, enabling the recruitment of neo-substrates, such as CK1α, and their degradation via the ubiquitinproteasome system. Here, we report FAM83F as such a neo-substrate. The eight FAM83 proteins (A-H) interact with and regulate the subcellular distribution of CK1α. We demonstrate that IMiD-induced FAM83F degradation requires its association with CK1α. However, no other FAM83 protein is degraded by IMiDs. We have recently identified FAM83F as a mediator of the canonical Wnt signalling pathway. The IMiD-induced degradation of FAM83F attenuated Wnt signalling in colorectal cancer cells and removed CK1α from the plasma membrane, mirroring the phenotypes observed with genetic ablation of FAM83F. Intriguingly, the expression of FAM83G, which also binds to CK1α, appears to attenuate the IMiD-induced degradation of CK1α, suggesting a protective role for FAM83G on CK1α. Our findings reveal that the efficiency and extent of target protein degradation by IMiDs depends on the nature of inherent multiprotein complex in which the target protein is part of.