TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains
TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains
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DOI：
10.1016/j.molcel.2021.01.023
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发表时间：
2021-04-01
期刊：
影响因子：
16
通讯作者：
Ohtake, Fumiaki
中科院分区：
文献类型：
--
作者：
Kaiho-Soma, Ai;Akizuki, Yoshino;Ohtake, Fumiaki
靶向蛋白降解是一种新兴的治疗模式。小分子降解剂如蛋白水解靶向嵌合体（PROTAC）通过劫持E3泛素连接酶诱导新底物的降解。尽管内源性底物的泛素化已被广泛研究，但新底物的强制降解的机制尚不清楚。我们发现泛素连接酶TRIP 12促进PROTAC诱导的和CRL 2（VHL）介导的BRD 4降解，但不促进内源性CRL 2（VHL）底物HIF-1 α的降解。TRIP 12通过CRL 2（VHL）与BRD 4结合并特异性组装K29连接的泛素链，促进K29/K48分支的泛素链的形成并加速通过CRL 2（VHL）组装K48连接。因此，TRIP 12促进PROTAC诱导的凋亡反应。TRIP 12还支持靶向CRABP 2或TRIM 24或募集CRBN的其他降解剂的效率。这些观察结果将TRIP 12和K29/K48分支泛素链定义为PROTAC指导的靶蛋白降解的加速剂，揭示了新底物降解所特有的分支泛素链组装的协同机制。
Targeted protein degradation is an emerging therapeutic paradigm. Small-molecule degraders such as proteolysis-targeting chimeras (PROTACs) induce the degradation of neo-substrates by hijacking E3 ubiquitin ligases, Although ubiquitylation of endogenous substrates has been extensively studied, the mechanism underlying forced degradation of neo-substrates is less well understood. We found that the ubiquitin ligase TRIP12 promotes PROTAC-induced and CRL2(VHL)-mediated degradation of BRD4 but is dispensable for the degradation of the endogenous CRL2(VHL )substrate HIF-1 alpha. TRIP12 associates with BRD4 via CRL2(VHL) and specifically assembles K29-linked ubiquitin chains, facilitating the formation of K29/K48-branched ubiquitin chains and accelerating the assembly of K48 linkage by CRL2(VHL). Consequently, TRIP12 promotes the PROTAC-induced apoptotic response. TRIP12 also supports the efficiency of other degraders that target CRABP2 or TRIM24 or recruit CRBN. These observations define TRIP12 and K29/K48-branched ubiquitin chains as accelerators of PROTAC-directed targeted protein degradation, revealing a cooperative mechanism of branched ubiquitin chain assembly unique to the degradation of neo-substrates.