Shin-biology regulated by protein lifetime

Grant-in-Aid for Transformative Research Areas (A) FY2023–FY2027, MEXT Japan

Planned Research

Protein lifetime dynamics in cell and organ senescence
Shigeo Murata  
Graduate School of Pharmaceutical Sciences, The University of Tokyo
Disruption of protein homeostasis is a universally observed phenomenon in aging individuals. Among the major pathways involved in protein homeostasis, age-dependent dysfunction of the proteasome, which is responsible for 70% of intracellular proteolysis, is thought to play an important role. Indeed, it has been shown that forced overexpression of proteasome components in budding yeast, worms, and fruit flies can enhance proteasome function, resulting in prolonged mitotic and individual lifespans. This demonstrates that proteasome activity directly regulates the lifespan of an organism. What kind of dynamic changes and accumulation of proteins occurs due to age-dependent proteasome dysfunction, and how do these changes affect organ dysfunction and individual aging? In recent years, analysis of proteomic changes during aging has been reported, particularly in C. elegans and Drosophila. However, the specific molecules that significantly influence mammalian aging are completely unknown. Senescent cells are not quiescent cells but are actively engaged in metabolic activities, including proteolysis, and exhibit the senescence-associated secretory phenotype (SASP), a secretory phenomenon associated with cellular senescence that promotes inflammation and carcinogenesis. However, little is known about which proteins are degraded by the proteasome in senescent cells and what role they play in the phenotype of senescent cells. In this study, we aim to elucidate the role of proteasomal proteolysis in senescent cells, analyze the dynamics of protein lifetime in different tissues due to age-dependent proteasome dysfunction and elucidate its pathophysiological significance, and based on this understanding, develop chemical tools to manipulate protein lifetime involved in aging.
  1. Takehara Y, Yashiroda H, Matsuo Y, Zhao X, Kamigaki A, Matsuzaki T, Kosako H, Inada T, *Murata S. The ubiquitination-deubiquitination cycle on the ribosomal protein eS7A is crucial for efficient translation. iScience. 24, 102145, 2021
  2. *Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, Mishima H, Kinoshita A, Mizushima T, Hamada S, Hamada K, Kawamoto N, Kadowaki S, Honda Y, Izawa K, Nishikomori R, Tsumura M, Yamashita Y, Tamura S, Orimo T, Ozasa T, Kato T, Sasaki I, Fukuda-Ohta Y, Wakaki-Nishiyama N, Inaba Y, Kunimoto K, Okada S, Taketani T, Nakanishi K, Murata S, Yoshiura KI, *Kaisho T. Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency. Nat Commun 12, 6819, 2021
  3. *Naito M, *Murata S. Gluing proteins for targeted degradation. Cancer Cell 24, 19-21, 2021
  4. Hashimoto E, Okuno S, Hirayama S, Arata Y, Goto T, Kosako H, Hamazaki J, *Murata S. Enhanced O-GlcNAcylation mediates cytoprotection under proteasome impairment by promoting proteasome turnover in cancer cells. iScience 23, 101299, 2020
  5. Arata Y, Watanabe A, Motosugi R, Murakami R, Goto T, Hori S, Hirayama S, Hamazaki J, *Murata S. Defective induction of the proteasome associated with T‐cell receptor signaling underlies T‐cell senescence. Genes Cells 24, 801–813, 2019
  6. Tomita T, Hirayama S, Sakurai Y, Ohte Y, Yoshihara H, Saeki Y, Hamazaki J, *Murata S. Specific modification of aged proteasomes revealed by tag-exchangeable knock-in mice. Mol Cell Biol 39, e00426-18, 2018
  7. *Murata S, Takahama Y, Kasahara M, Tanaka K. The immunoproteasome and thymoproteasome: functions, evolutions and human disease. Nat Immunol 19, 923-931, 2018
  8. Uechi H, Kuranaga E, Iriki T, Takano K, Hirayama S, Miura M, Hamazaki J, *Murata S. Ubiquitin-binding protein CG5445 suppresses aggregation and cytotoxicity of amyotrophic lateral sclerosis-linked TDP43 in Drosophila. Mol Cell Biol. 38, e00195-17, 2018
  9. Ohigashi I, Ohte Y, Setoh K, Nakase H, Maekawa A, Kiyonari H, Hamazaki Y, Sekai M, Sudo T, Tabara Y, Sawai H, Omae Y, Yuliwulandari R, Tanaka Y, Mizokami M, Inoue H, Kasahara M, Minato N, Tokunaga K, Tanaka K, Matsuda F, Murata S, *Takahama Y. A human PSMB11 variant affects thymoproteasome processing and CD8+ T cell production. JCI Insight 2, e93664, 2017
  10. Uddin MM, Ohigashi I, Motosugi R, Nakayama T, Sakata M, Hamazaki J, Nishito Y, Rode I, Tanaka K, Takemoto T, *Murata S, *Takahama Y. Foxn1-β5t transcriptional axis controls CD8+ T-cell production in the thymus. Nat Commun 8, 14419, 2017