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

• Published in: Molecular cell Vol. 81; no. 7; pp. 1411 - 1424.e7
• Main Authors: Kaiho-Soma, Ai, Akizuki, Yoshino, Igarashi, Katsuhide, Endo, Akinori, Shoda, Takuji, Kawase, Yasuko, Demizu, Yosuke, Naito, Mikihiko, Saeki, Yasushi, Tanaka, Keiji, Ohtake, Fumiaki
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2021
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; apoptosis; cancer; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; cullin-RING ligase; epigenetics; HCT116 Cells; HEK293 Cells; Humans; Hypoxia-Inducible Factor 1, alpha Subunit - genetics; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Polyubiquitin - genetics; Polyubiquitin - metabolism; protein degradation; Proteolysis; Receptors, Cytokine - genetics; Receptors, Cytokine - metabolism; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; targeted protein degradation; therapeutics; Transcription Factors - genetics; Transcription Factors - metabolism; ubiquitin; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; ubROTAC; ubROTAC; cullin-RING ligase; targeted protein degradation; apoptosis; cancer; epigenetics; ubiquitin
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2021.01.023

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. [Display omitted] •TRIP12 facilitates PROTAC-induced and CRL2VHL-mediated degradation of BRD4•TRIP12 specifically assembles K29-linked Ub chains•TRIP12 and CRL2VHL cooperatively assemble K29/K48-branched Ub chains on BRD4•Targeted degradation uses unique mechanisms rather than a simple “hijack” Targeted protein degradation is an emerging therapeutic paradigm. Kaiho-Soma et al. found that the K29-linkage specific ubiquitin ligase TRIP12 promotes small-molecule-induced and CRL2-mediated degradation of neo-substrates such as BRD4. They identified K29/K48-branched ubiquitin chains as a ubiquitin code used for chemically induced targeted protein degradation.