TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains

被引：66

作者：

Kaiho-Soma, Ai ^{[1
]}

Akizuki, Yoshino ^{[2
]}

Igarashi, Katsuhide ^{[1
,2
]}

Endo, Akinori ^{[3
]}

Shoda, Takuji ^{[4
]}

Kawase, Yasuko ^{[3
]}

Demizu, Yosuke ^{[4
]}

Naito, Mikihiko ^{[4
,5
]}

Saeki, Yasushi ^{[3
]}

Tanaka, Keiji ^{[3
]}

Ohtake, Fumiaki ^{[1
,2
,3
]}

机构：

[1] Hoshi Univ, Inst Adv Life Sci, Shinagawa Ku, 2-4-41 Ebara, Tokyo 1428501, Japan

[2] Hoshi Univ, Sch Pharm & Pharmaceut Sci, Shinagawa Ku, 2-4-41 Ebara, Tokyo 1428501, Japan

[3] Tokyo Metropolitan Inst Med Sci, Prot Metab Project, Setagaya Ku, 2-1-6 Kamikitazawa, Tokyo 1568506, Japan

[4] Natl Inst Hlth Sci, Div Organ Chem, Kawasaki Ku, 3-25-26 Tonomachi, Kawasaki, Kanagawa 2109501, Japan

[5] Natl Inst Hlth Sci, Div Mol Target & Gene Therapy Prod, Kawasaki Ku, 3-25-26 Tonomachi, Kawasaki, Kanagawa 2109501, Japan

来源：

MOLECULAR CELL | 2021年 / 81卷 / 07期

关键词：

apoptosis; cancer; cullin-RING ligase; epigenetics; targeted protein degradation; ubiquitin; ubROTAC;

D O I：

10.1016/j.molcel.2021.01.023

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1411 / +

页数：21

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