Ubiquitin ligase marks neo-substrates for degradation with unique Ub code.

Targeted protein degradation has recently been studied as a possible therapeutic paradigm. Kaiho-Soma et al. were able to establish that the ubiquitin ligase thyroid hormone receptor-interacting protein 12 (TRIP12) accelerates the degradation of neo-substrates like BRD4 through a complex mechanism induced by the small-molecule degrader PROTAC and mediated by the substrate specific adapter ligase complex CRL2VHL.

In this study, the absolute quantification of ubiquitin linkages (Ub-AQUA/PRM) was performed by using LC-MS and peptides. Peptides were separated on an IonOpticks Aurora Series emitter column.

TRIP12 and K29/K48-branched ubiquitin chains were identified as accelerators of PROTAC-directed targeted protein degradation by acting as a unique code, revealing a cooperative mechanism of branched ubiquitin chain assembly unique to the degradation of neo-substrates.

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. In response TRIP12 has been observed to promote the PROTAC-induced apoptotic response. An additional attribute of TRIP12 is seen that it also supports other degraders that target CRABP2 or TRIM24. 

In the future the discovered PROTAC coregulatory mechanism could be fine tuned for targeted proteins degradation of cancer cells.

Read the full paper
TRIP12 promotes small-molecule-induced degradation through K29/K48-branched ubiquitin chains.
Mol Cell. 2021;S1097-2765(21)00043-5. doi: https://www.cell.com/molecular-cell/pdf/S1097-2765(21)00043-5.pdf
Kaiho-Soma A, Akizuki Y, Igarashi K, Endo A, Shoda T, Kawase Y, Demizu Y, Naito M, Saeki Y, Tanaka K, Ohtake F.

Commentary by Amr S Abbadi, PhD candidate.

About the author
Amr is a PhD candidate in comparative biomedical sciences at the University of Georgia, USA. He has also worked as a freelance writer and digital marketer for five years. Amr received his MSc in Pharmaceutical Biotechnology from the University of Padova in Italy, and graduated from the Suez Canal University in Egypt with a BSc in Clinical Pharmacy.