Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species
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 <i>Caenorhabditis elegans</i>. We show that Pelota mitigates premature senescence in cultured human cells, muscle aging in mice, and neuropathology in cellular and organoid models of Alzheimer'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.
Authors
- Seokjin Ham (ORCID: https://orcid.org/0000-0002-6950-2848)
- Gee‐Yoon Lee (ORCID: https://orcid.org/0000-0002-4142-8842)
- Hanseul Lee (ORCID: https://orcid.org/0000-0003-1800-2701)
- Hyemin Min (ORCID: https://orcid.org/0000-0001-9691-770X)
- Jinsoo Seo (ORCID: https://orcid.org/0000-0001-6432-6964)
- Sujeong Kwon
- Eun Seok Kang (ORCID: https://orcid.org/0000-0002-0364-4675)
- Hyunwoo C. Kwon
- Chunghun Lim
- Eun Ji E. Kim
- Yoonji Jung (ORCID: https://orcid.org/0000-0003-1557-2645)
- Kwang‐Pyo Lee (ORCID: https://orcid.org/0000-0003-0067-6898)
- Sang‐Soon Park (ORCID: https://orcid.org/0000-0002-5008-1609)
- Tatiana M. Moreno (ORCID: https://orcid.org/0000-0002-7466-2491)
- Sieun S. Kim
- Seokjun G. Ha (ORCID: https://orcid.org/0000-0002-6727-7851)
- Yeo Jin Shin
- Chanhee Kang (ORCID: https://orcid.org/0000-0003-4350-5706)
- Heeju Park
- Molly E. Brown (ORCID: https://orcid.org/0000-0001-7384-3314)
- Caroline Kumsta (ORCID: https://orcid.org/0000-0003-3839-4888)
- Hae‐Eun H. Park
- Jongsun Lee
- Seung‐Jae Lee (ORCID: https://orcid.org/0000-0002-6103-156X)
- Bora Lee (ORCID: https://orcid.org/0000-0002-6322-5712)
- Hyein Lee
- Jae Won Yang (ORCID: https://orcid.org/0000-0003-3689-5865)
- Eunah Kim
- Waun Ki Hong (ORCID: https://orcid.org/0009-0008-9329-5544)
- Syh-Yuan Hwang (ORCID: https://orcid.org/0009-0009-5806-3905)
Institutions
- Seoul National University (KR)
- Korea Advanced Institute of Science and Technology (KR)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Yonsei University (KR)
- Discovery Institute (US)
- Ulsan National Institute of Science and Technology (KR)
- Korea Research Institute of Bioscience and Biotechnology (KR)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-08-04
- DOI
- https://doi.org/10.1073/pnas.2505217122
- Citations
- 5
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 4.03
Funders
- National Research Foundation of Korea