TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains.
Mol Cell
; 81(7): 1411-1424.e7, 2021 04 01.
Article
em En
| MEDLINE
| ID: mdl-33567268
ABSTRACT
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Proteínas de Transporte
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Poliubiquitina
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Ubiquitina-Proteína Ligases
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Proteólise
Limite:
Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article