Mallory-Denk bodies-like inclusion body isolates misfolded aggregated proteins and regulates intracellular signaling pathway

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07926
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Harada Masaru 産業医科大学, 医学部, 教授 (00241175)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 細胞内封入体 / p62/SQSTM1 / 酸化ストレス / 商法お対ストレス / オートファジー / Nrf2

Outline of Final Research Achievements

Proteasome inhibition induced Mallory-Denk body like inclusions isolates harmful misfolded protein aggregates positive for ubiquitin, because disruption of inclusion body formation deteriorated oxidative stress and endoplasmic reticulum stress. It also activated autophay. Proteasome inhibition induced accumulation of p62 accelerated Nrf2-HO-1 antioxidant pathway. Disruption of inclusion formation increased cytosolic p62 and accelerated Nrf2 regulated antioxidant pathway. These results indicate that inclusion bodies including Mallory-Denk body regulates intracellular signaling pathway as well as isolates harmful misfolded protein aggregates.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

代謝異常関連脂肪性肝疾患(MASLD)は現在大変注目されている。これは肝不全の原因になるのみでなく肝細胞癌にも進展する。これまでMASLDによく関連する肝細胞内封入体であるMallory-Denk体の細胞障害や細胞増殖への役割を検討した仕事は我々のグループの仕事のみである。これによりMASLDの関連する肝不全や肝細胞癌の発症機序の一部が明らかとなった。