Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development.
Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development.
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DOI：
10.1172/jci129374
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发表时间：
2020-09
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通讯作者：
Kai Song;Xiaofeng S Cai;Yunzhou Dong;Hao Wu;Yong Wei;U. Shankavaram;Kui Cui;Yang Lee;Bo Zhu;Sudarshan Bhattacharjee;Beibei Wang;Kun Zhang;Aiyun Wen;Scott W. Wong;Lili Yu;Lijun Xia;A. Welm;D. Bielenberg;K. Camphausen;Yibin Kang;Hong Chen
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作者：
Kai Song;Xiaofeng S Cai;Yunzhou Dong;Hao Wu;Yong Wei;U. Shankavaram;Kui Cui;Yang Lee;Bo Zhu;Sudarshan Bhattacharjee;Beibei Wang;Kun Zhang;Aiyun Wen;Scott W. Wong;Lili Yu;Lijun Xia;A. Welm;D. Bielenberg;K. Camphausen;Yibin Kang;Hong Chen
雌激素受体(ER)阴性的乳腺癌被认为比ER阳性的乳腺癌更恶性和破坏性更强，并表现出高水平的NF-κB活性。ER阴性乳腺癌中如何维持异常高的NF-κB活性目前还知之甚少。线性泛素化是由线性泛素链组装复合体产生的，在调节细胞激活和死亡的NF-κB信号中的重要性越来越受到重视。在这里，我们证明了epsin蛋白是一个泛素结合的内吞适配器家族，通过其泛素相互作用基序(UIM)与LUBAC相互作用，并通过其N-末端同源(第10)结构域与LUBAC的真正底物NEMO结合。此外，EPSINS促进了NF-κB必需调节剂(NEMO)的线性泛素化，并作为支架招募IκB激酶(IKK)复合体的其他成分，从而导致IKK活性增强和持续的NF-κB信号转导，对ER阴性乳腺癌的发展至关重要。雌激素受体阴性的人乳腺癌中高水平的内皮素水平与较差的无复发生存率有关。在自发性和患者来源的异种乳腺癌小鼠模型中，我们显示了转基因和药物方法消除epins有效地阻碍了乳腺癌的发展。我们的发现证实了epsins在促进乳腺癌中所起的关键作用。因此，靶向EPSIN可能代表了一种抑制NF-κB信号转导的策略，并为ER阴性乳腺癌的治疗提供了一个重要的前景。
Estrogen receptor (ER)-negative breast cancer is thought to be more malignant and devastating than ER-positive breast cancer and exhibit elevated NF-κB activity. How abnormally high NF-κB activity is maintained in ER-negative breast cancer is poorly understood. The importance of linear ubiquitination, which is generated by the linear ubiquitin chain assembly complex (LUBAC), is increasingly appreciated in NF-κB signaling, which regulates cell activation and death. Here, we showed that epsin proteins, a family of ubiquitin-binding endocytic adaptors, interacted with LUBAC via its Ubiquitin-Interacting Motif (UIM) and bound LUBAC's bona fide substrate NEMO via its N-terminal homolog (ENTH) domain. Furthermore, epsins promoted NF-κB essential modulator (NEMO) linear ubiquitination and served as scaffolds for recruiting other components of the IκB kinase (IKK) complex; thereby, resulting in the heightened IKK activation and sustained NF-κB signaling essential for the development of ER-negative breast cancer. Heightened epsin levels in ER-negative human breast cancer are associated with poor, relapse-free survival. We showed that transgenic and pharmacological approaches eliminating epsins potently impeded breast cancer development in both spontaneous and patient-derived xenograft breast cancer mouse models. Our findings established the pivotal role epsins played in promoting breast cancer. Thus, targeting epsins may represent a strategy to restrain NF-κB signaling, and provide an important perspective into ER-negative breast cancer treatment.