Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species

• 成果类型: Article
• 署名作者: Lee, Jongsun; Lee, Bora; Lee, Hyein; Kim, Eun Ji E.; Kim, Sieun S.; Kwon, Hyunwoo C.; Lee, Hanseul; Lee, Gee - Yoon; Hong, Woojin; Ham, Seokjin; Yang, Jae Won; Park, Heeju; Moreno, Tatiana M.; Brown, Michelle E.; Park, Hae- Eun H.; Kim, Eunah; Jung, Yoonji; Kang, Eunseok; Park, Sangsoon; Shin, Yeo Jin; Ha, Seokjun G.; Kwon, Sujeong; Hwang, Seungjae; Min, Hyemin; Kumsta, Caroline; Lim, Chunghun; Kang, Chanhee; Seo, Jinsoo; Lee, Kwang-Pyo; Leea, Seung-Jae, V
• 署名单位: Korea Advanced Institute of Science & Technology (KAIST); Korea Research Institute of Bioscience & Biotechnology (KRIBB); Daegu Gyeongbuk Institute of Science & Technology (DGIST); Yonsei University; Korea Research Institute of Bioscience & Biotechnology (KRIBB); University of Science & Technology (UST); University of Science & Technology (UST); Ulsan National Institute of Science & Technology (UNIST); Sanford Burnham Prebys Medical Discovery Institute; Sanford Burnham Prebys Medical Discovery Institute; Seoul National University (SNU)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14255
• DOI: 10.1073/pnas.2505217122
• 发表日期: 2025-08-12
• 关键词: messenger-rna; life-span; autophagy; senescence; longevity; dissociation; degradation; initiation; biomarker; protein

摘要

Ribosome-associated quality control (RQC) is a pivotal biological process that governs the fidelity of messenger RNA (mRNA) homeostasis and protein synthesis. Defects in RQC are implicated in cellular dysfunction and proteotoxicity, but their impact on aging remains elusive. Here, we show that Pelota, the ribosome rescue factor, promotes longevity and protects against age-related pathological phenotypes in multiple metazoan species. By performing a targeted genetic screen, we find that Pelota is indispensable for longevity in the nematode Caenorhabditis elegans. We show that Pelota mitigates premature senescence in cultured human cells, muscle aging in mice, and neuropathology in cellular and organoid models ofAlzheimer's disease. Mechanistically, we demonstrate that Pelota maintains autophagy-mediated proteostasis, by preventing the hyperactivation of mechanistic target of rapamycin signaling. Overall, our work highlights the conserved functional significance of RQC, regulated by Pelota, in extending lifespan and protecting diverse species against age-associated disease phenotypes.