TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains.
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-1?. 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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Carrier Proteins, Cell Cycle Proteins, HCT116 Cells, HEK293 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Polyubiquitin, Proteolysis, Receptors, Cytokine, Receptors, Retinoic Acid, Transcription Factors, Ubiquitin-Protein Ligases
Adaptor Proteins, Signal Transducing, Carrier Proteins, Cell Cycle Proteins, HCT116 Cells, HEK293 Cells, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Polyubiquitin, Proteolysis, Receptors, Cytokine, Receptors, Retinoic Acid, Transcription Factors, Ubiquitin-Protein Ligases
Mol Cell
Date: Dec. 01, 2020
PubMed ID: 33567268
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