biostudies-literatureMori YMEXT | Japan Society for the Promotion of ScienceMEXT | Japan Society for the Promotion of Science (JSPS)Japan Agency for Medical Research and DevelopmentJapan Agency for Medical Research and Development (AMED)5379https://www.ebi.ac.uk/biostudies/studies/S-EPMC11220168biostudies-literatureUnknown15(1)Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2^VHL- or CRL4^CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and foNature communicationsIntrinsic signaling pathways modulate targeted protein degradation.PMC11220168JP20K2140821458950JP18H05498JP21H02433Iio HSaeki YUshijima TMori YTsuchimoto AOhtake FAkizuki YKaiho-Soma AHonda RHashimoto SKato MHamazaki JTakao MHattori NMurata SfalseIntrinsic signaling pathways modulate targeted protein degradation.Targeted protein degradation is a groundbreaking modality in drug discovery; however, the regulatory mechanisms are still not fully understood. Here, we identify cellular signaling pathways that modulate the targeted degradation of the anticancer target BRD4 and related neosubstrates BRD2/3 and CDK9 induced by CRL2^VHL- or CRL4^CRBN -based PROTACs. The chemicals identified as degradation enhancers include inhibitors of cellular signaling pathways such as poly-ADP ribosylation (PARG inhibitor PDD00017273), unfolded protein response (PERK inhibitor GSK2606414), and protein stabilization (HSP90 inhibitor luminespib). Mechanistically, PARG inhibition promotes TRIP12-mediated K29/K48-linked branched ubiquitylation of BRD4 by facilitating chromatin dissociation of BRD4 and fo2024-01-01T00:00:00Z2024 Jul2026-07-15T10:30:23.782Z2025-04-04T12:54:50.769ZS-EPMC112201683895605210.1038/s41467-024-49519-z