Intrinsic signaling pathways modulate targeted protein degradation.
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
Nature communications, 02 Jul. 2024
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 CRL2VHL- or CRL4CRBN -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 formation of the BRD4-PROTAC-CRL2VHL ternary complex; by contrast, HSP90 inhibition promotes BRD4 degradation after the ubiquitylation step. Consequently, these signal inhibitors sensitize cells to the PROTAC-induced apoptosis. These results suggest that various cell-intrinsic signaling pathways spontaneously counteract chemically induced target degradation at multiple steps, which could be liberated by specific inhibitors.

Senescent cells form nuclear foci that contain the 26S proteasome.
Tomohiro Iriki; Hiroaki Iio; Shu Yasuda; Shun Masuta; Masakazu Kato; Hidetaka Kosako; Shoshiro Hirayama; Akinori Endo; Fumiaki Ohtake; Mako Kamiya; Yasuteru Urano; Yasushi Saeki; Jun Hamazaki; Shigeo Murata
Cell reports, 01 Aug. 2023
The proteasome plays a central role in intracellular protein degradation. Age-dependent decline in proteasome activity is associated with cellular senescence and organismal aging; however, the mechanism by which the proteasome plays a role in senescent cells remains elusive. Here, we show that nuclear foci that contain the proteasome and exhibit liquid-like properties are formed in senescent cells. The formation of senescence-associated nuclear proteasome foci (SANPs) is dependent on ubiquitination and RAD23B, similar to previously known nuclear proteasome foci, but also requires proteasome activity. RAD23B knockdown suppresses SANP formation and increases mitochondrial activity, leading to reactive oxygen species production without affecting other senescence traits such as cell-cycle arrest and cell morphology. These findings suggest that SANPs are an important feature of senescent cells and uncover a mechanism by which the proteasome plays a role in senescent cells.

細胞老化に伴う新規プロテアソーム核内foci SANPs(senescence-associated nuclear proteasome foci)の発見
2023

Analysis of the proteostasis in mice with increased proteasome activity by DDI2 overexpression　　　　　　　　　　　　　　　
2022

The augmentation of the tumor-specific accumulation of live-Bifidobacteria by the enhancing agent for EPR effect.　　　　　　　　　　　　　　　
2019

TNF-α発現・分泌組換えビフィズス菌のマウス悪性黒色腫モデルを用いたがん免疫療法への応用検討　　　　　　　　　　　　　　　
加藤 雅和; 平 裕一郎; 平 郁子; 清水 芳実; 磯田 勝広; 斎藤 浩美; 石田 功
日本薬学会年会要旨集, Mar. 2018
(公社)日本薬学会

TNF-α発現・分泌組換えビフィズス菌の構築及び抗腫瘍効果の検討　　　　　　　　　　　　　　　
Sep. 2017

2019 - Present
The Molecular Biology Society of Japan　　　　　　　　　　　　　　　

2019 - Present
The Japanese Biochemical Society　　　　　　　　　　　　　　　

2017 - Present
The Pharmaceutical Society of Japan