The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling.
The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling.
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DOI：
10.1038/s41467-021-25634-z
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发表时间：
2021-09-06
影响因子：
16.6
通讯作者：
Robbins DJ
中科院分区：
文献类型：
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作者：
Shen C;Nayak A;Neitzel LR;Adams AA;Silver-Isenstadt M;Sawyer LM;Benchabane H;Wang H;Bunnag N;Li B;Wynn DT;Yang F;Garcia-Contreras M;Williams CH;Dakshanamurthy S;Hong CC;Ayad NG;Capobianco AJ;Ahmed Y;Lee E;Robbins DJ
免疫调节药物（IMiD）对于治疗多发性骨髓瘤和骨髓增生异常综合征很重要。 IMiD 与 Cereblon (CRBN)（CRL4CRBN E3 泛素连接酶的底物受体）结合，通过靶向关键的新底物降解来诱导癌细胞死亡。尽管具有这种临床意义，CRBN 的生理调节仍然很大程度上未知。在此，我们证明 Wnt（重要信号转导途径的细胞外配体）可促进部分蛋白质的 CRBN 依赖性降解。这些底物包括酪蛋白激酶 1α (CK1α)，它是 Wnt 信号传导的负调节因子，是 β-连环蛋白破坏复合物的关键组成部分。 Wnt 刺激诱导 CRBN 与 CK1α 相互作用及其产生的泛素化，与之前的报道相反，它是在没有 IMiD 的情况下发生的。从机制上讲，破坏复合物对于在 Wnt 缺失的情况下维持 CK1α 稳定性以及招募 CRBN 靶向 CK1α 以响应 Wnt 进行降解至关重要。 CRBN 是生理 Wnt 信号传导所必需的，因为斑马鱼和果蝇中 CRBN 的调节会产生 Wnt 驱动的表型。这些研究证明了 CRBN 调节的独立于 IMiD、Wnt 驱动的机制，并提供了一种通过 CRBN 控制 Wnt 通路活性的方法，与发育和疾病相关。 Cereblon (CRBN) 是一种 E3 泛素连接酶底物受体，参与癌细胞死亡，但其调控机制尚不清楚。在这里，作者表明 Wnt 配体会增加 CRBN 依赖性蛋白质降解，并证明 CRBN 在生理 Wnt 信号传导中的重要性。
Immunomodulatory drugs (IMiDs) are important for the treatment of multiple myeloma and myelodysplastic syndrome. Binding of IMiDs to Cereblon (CRBN), the substrate receptor of the CRL4CRBN E3 ubiquitin ligase, induces cancer cell death by targeting key neo-substrates for degradation. Despite this clinical significance, the physiological regulation of CRBN remains largely unknown. Herein we demonstrate that Wnt, the extracellular ligand of an essential signal transduction pathway, promotes the CRBN-dependent degradation of a subset of proteins. These substrates include Casein kinase 1α (CK1α), a negative regulator of Wnt signaling that functions as a key component of the β-Catenin destruction complex. Wnt stimulation induces the interaction of CRBN with CK1α and its resultant ubiquitination, and in contrast with previous reports does so in the absence of an IMiD. Mechanistically, the destruction complex is critical in maintaining CK1α stability in the absence of Wnt, and in recruiting CRBN to target CK1α for degradation in response to Wnt. CRBN is required for physiological Wnt signaling, as modulation of CRBN in zebrafish and Drosophila yields Wnt-driven phenotypes. These studies demonstrate an IMiD-independent, Wnt-driven mechanism of CRBN regulation and provide a means of controlling Wnt pathway activity by CRBN, with relevance for development and disease. Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that is involved in cancer cell death, although its regulation is poorly understood. Here, the authors show that Wnt ligand increases CRBN-dependent protein degradation and demonstrate CRBN’s importance in physiological Wnt signaling.