cIAP1-based degraders induce degradation via branched ubiquitin architectures
cIAP1-based degraders induce degradation via branched ubiquitin architectures
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DOI：
10.1038/s41589-022-01178-1
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发表时间：
2022-10-31
影响因子：
14.8
通讯作者：
Ohtake, Fumiaki
中科院分区：
文献类型：
--
作者：
Akizuki, Yoshino;Morita, Mai;Ohtake, Fumiaki
通过E3泛素连接酶的化学劫持来靶向蛋白质降解是精准医学中的一个新兴概念。泛素密码是底物命运的关键决定因素。尽管两个E3，CRL 2（VHL）和CRL 4（CRBN），经常与蛋白水解靶向嵌合体（PROTAC）组装，以连接赖氨酸-48（K48）连接的泛素链，但用于化学诱导降解的泛素密码子的多样性在很大程度上是未知的。在这里，我们表明cIAP 1靶向降解剂的功效取决于K63特异性E2酶UBE 2N。UBE 2N促进cIAP 1配体诱导的cIAP 1降解和随后的癌细胞凋亡。从机制上讲，UBE 2N催化的K63连接的泛素链促进高度复杂的K48/K63和K11/K48分支泛素链的组装，从而招募p97/VCP，UCH 37和蛋白酶体。由cIAP 1募集PROTAC指导的新底物降解也依赖于UBE 2N。这些结果揭示了K63连接的泛素链和UBE 2N在降解物诱导的蛋白酶体降解中的意想不到的作用，并证明了用于化学劫持的泛素代码的多样性。
Targeted protein degradation through chemical hijacking of E3 ubiquitin ligases is an emerging concept in precision medicine. The ubiquitin code is a critical determinant of the fate of substrates. Although two E3s, CRL2(VHL) and CRL4(CRBN), frequently assemble with proteolysis-targeting chimeras (PROTACs) to attach lysine-48 (K48)-linked ubiquitin chains, the diversity of the ubiquitin code used for chemically induced degradation is largely unknown. Here we show that the efficacy of cIAP1-targeting degraders depends on the K63-specific E2 enzyme UBE2N. UBE2N promotes degradation of cIAP1 induced by cIAP1 ligands and subsequent cancer cell apoptosis. Mechanistically, UBE2N-catalyzed K63-linked ubiquitin chains facilitate assembly of highly complex K48/K63 and K11/K48 branched ubiquitin chains, thereby recruiting p97/VCP, UCH37 and the proteasome. Degradation of neo-substrates directed by cIAP1-recruiting PROTACs also depends on UBE2N. These results reveal an unexpected role for K63-linked ubiquitin chains and UBE2N in degrader-induced proteasomal degradation and demonstrate the diversity of the ubiquitin code used for chemical hijacking.