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

Ai Kaiho-Soma, Yoshino Akizuki, Katsuhide Igarashi, Akinori Endo, Takuji Shoda, Yasuko Kawase, Yosuke Demizu, Mikihiko Naito, Yasushi Saeki, Keiji Tanaka, Fumiaki Ohtake

Molecular cell 2021 Apr 01

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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 CRL2VHL-mediated degradation of BRD4 but is dispensable for the degradation of the endogenous CRL2VHL substrate HIF-1α. TRIP12 associates with BRD4 via CRL2VHL and specifically assembles K29-linked ubiquitin chains, facilitating the formation of K29/K48-branched ubiquitin chains and accelerating the assembly of K48 linkage by CRL2VHL. 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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

Ai Kaiho-Soma, Yoshino Akizuki, Katsuhide Igarashi, Akinori Endo, Takuji Shoda, Yasuko Kawase, Yosuke Demizu, Mikihiko Naito, Yasushi Saeki, Keiji Tanaka, Fumiaki Ohtake. TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains. Molecular cell. 2021 Apr 01;81(7):1411-1424.e7