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김은지Eun Ji E. Kim

KAIST

Proc. Natl. Acad. Sci. USA, Aug 12 2025, 122 (32) | https://doi.org/10.1073/pnas.2505217122 Pelota-mediated ribosome-associated quality control counteracts aging and age-associated pathologies across species

Jongsun Lee^a,1, Bora Lee^b,1, Hyein Lee^c,d,1, Eun Ji E. Kim^a,1, Sieun S. Kim^a, Hyunwoo C. Kwon^a, Hanseul Lee^a, Gee-Yoon Lee^a, Woojin Hong^a, Seokjin Ham^a, Jae Won Yang^b,e, Heeju Park^f, Tatiana M. Moreno^g,h, Michelle E. Brown^h, Hae-Eun H. Park^a, Eunah Kim^a, Yoonji Jung^a, Eunseok Kang^a, Sangsoon Park^a, Yeo Jin Shin^b, Seokjun G. Ha^a, Sujeong Kwon^a, Seungjae Hwang^a, Hyemin Min^a, Caroline Kumsta^h, Chunghun Lim^a, Chanhee Kangⁱ, Jinsoo Seo^c,d,2, Kwang-Pyo Lee^b,e,2, and Seung-Jae V. Lee^a,2

^aDepartment of Biological Sciences, Korea Advanced Institute of Scienceand Technology, Yuseong-gu, Daejeon 34141, South Korea;
^bAging Convergence ResearchCenter, Korea Research Institute of Bioscience and Biotechnology, Yuseong-gu, Daejeon34141, South Korea;
^cDepartment of Brain Sciences, Daegu Gyeongbuk Institute of Scienceand Technology, Hyeonpung-eup, Dalseong-gun, Daegu 42988, South Korea;
^dDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea;
^eDepartment of Bioscience, Korea Research Institute of Bioscience and Biotechnology School, Korea University of Science and Technology, Yuseong-gu, Daejeon 34113, South Korea;

^fDepartment of Biological Sciences, Ulsan National Institute of Science and Technology, Ulsan 44919, South Korea;
^gGraduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037;
^hSanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037; and
ⁱSchool of Biological Sciences, Seoul National University, Gwanak-gu, Seoul 08826, South Korea

¹J.L., B.L., Hyein Lee, and E.J.E.K. contributed equally tothis work.
²To whom correspondence may be addressed. : Jinsoo Seo, Kwang-Pyo Lee, and Seung-Jae V. Lee

Abstract

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 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.

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