Schematic model. Modified from: Mori et al., 2024. “Intrinsic signaling pathways modulate targeted protein degradation”, Nat Commun 15, 5379 (2024). Licensed under an Attribution 4.0 international license.

New research from Mori et al. sheds light on the cellular pathways that modulate targeted protein degradation induced by PROTACs (proteolysis targeting chimeras).

The researchers conducted a chemical screen and identified inhibitors of PARG, PERK, and HSP90 as enhancers of PROTAC-mediated degradation of BRD family proteins. One finding was that PARG inhibition promotes the formation of the BRD4-PROTAC-CRL2 [superscript: VHL] ternary complex and enhances K29/K48-branched ubiquitylation of BRD4.

ChIP-seq analysis revealed that PARG inhibition facilitates BRD4 dissociation from chromatin, likely contributing to enhanced degradation. PERK inhibition was shown to promote BRD4 ubiquitylation, while HSP90 inhibition affected a step downstream of ubiquitylation.

The researchers also demonstrated that these inhibitors sensitize cancer cells to PROTAC-induced apoptosis and enhance the efficacy of highly potent PROTACs. Furthermore, they found that these enhancers can be applied to other neosubstrates beyond BRD family proteins.

This study is significant as it reveals that cell-intrinsic pathways can counteract targeted protein degradation at multiple steps, providing new insights into the mechanisms of PROTAC-induced degradation and potential strategies to improve their efficacy.

The IonOpticks Aurora Ultimate 25×75 C18 UHPLC column enabled high-resolution LC-MS/MS analysis for precise quantification of ubiquitin linkages, which was essential for elucidating the underlying mechanisms of enhanced protein degradation.

Publication
Nature Communications

Authors

Yuki Mori, Yoshino Akizuki, Rikuto Honda, Miyu Takao, Ayaka Tsuchimoto, Sota Hashimoto, Hiroaki Iio, Masakazu Kato, Ai Kaiho-Soma, Yasushi Saeki, Jun Hamazaki, Shigeo Murata, Toshikazu Ushijima, Naoko Hattori & Fumiaki Ohtake

Title

Intrinsic signaling pathways modulate targeted protein degradation