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

Mol Cell. 2021 Apr 1;81(7):1411-1424.e7. doi: 10.1016/j.molcel.2021.01.023. Epub 2021 Feb 9.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Polyubiquitin / genetics
  • Polyubiquitin / metabolism*
  • Proteolysis*
  • Receptors, Cytokine / genetics
  • Receptors, Cytokine / metabolism
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*


  • Adaptor Proteins, Signal Transducing
  • BRD4 protein, human
  • CRBN protein, human
  • CRLF2 protein, human
  • Carrier Proteins
  • Cell Cycle Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Cytokine
  • Receptors, Retinoic Acid
  • TRIM24 protein, human
  • Transcription Factors
  • retinoic acid binding protein II, cellular
  • Polyubiquitin
  • TRIP12 protein, human
  • Ubiquitin-Protein Ligases