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

doi:10.1016/j.celrep.2023.112880

Senescent cells form nuclear foci that contain the 26S proteasome

Cell Rep. 2023 Aug 29;42(8):112880. doi: 10.1016/j.celrep.2023.112880. Epub 2023 Aug 3.

Authors

Affiliations

¹ Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan.
² Department of Hygienic Chemistry and Medical Research Laboratories, School of Pharmaceutical Sciences, Kitasato University, Minato-ku, Tokyo 1088641, Japan.
³ Faculty of Pharmaceutical Sciences, Teikyo Heisei University, Nakano-ku, Tokyo 1648530, Japan.
⁴ Division of Cell Signaling, Fujii Memorial Institute of Medical Sciences, Tokushima University, Kuramoto-cho, Tokushima 7708503, Japan.
⁵ Laboratory of Protein Metabolism, Tokyo Metropolitan Institute of Medical Science, Setagaya-ku, Tokyo 1568506, Japan.
⁶ Institute for Advanced Life Sciences, Hoshi University, Shinagawa-ku, Tokyo 1428501, Japan.
⁷ Department of Life Science and Technology, Tokyo Institute of Technology, Midori-ku, Yokohama 2268501, Japan.
⁸ Laboratory of Chemical Biology and Molecular Imaging, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan; Laboratory of Chemical Biology and Molecular Imaging, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan.
⁹ Division of Protein Metabolism, the Institute of Medical Science, the University of Tokyo, Minato-ku, Tokyo 1088639, Japan.
¹⁰ Laboratory of Protein Metabolism, Graduate School of Pharmaceutical Sciences, the University of Tokyo, Bunkyo-ku, Tokyo 1130033, Japan. Electronic address: smurata@mol.f.u-tokyo.ac.jp.

PMID: 37541257
DOI: 10.1016/j.celrep.2023.112880

Abstract

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.

Keywords: CP: Cell biology; CP: Molecular biology; cell senescence; liquid-liquid phase separation; mitochondria; nuclear body; proteasome; ubiquitin.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Nucleus* / metabolism
Cellular Senescence
Proteasome Endopeptidase Complex* / metabolism
Ubiquitination

Substances

ATP dependent 26S protease
Proteasome Endopeptidase Complex