Phosphorylation of an <scp>RNA</scp>‐Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging

The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. In this study, we report that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism.

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Journal
Aging Cell
Published
2025-03-11
DOI
https://doi.org/10.1111/acel.70022
Citations
5
Primary Topic
Genetics, Aging, and Longevity in Model Organisms
Type
article
Field-Weighted Citation Impact
4.77

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article

Phosphorylation of an RNA‐Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging

Eunbyul Yeom, Eun‐Soo Kwon, Jason S. Pierce, Yoo Lim Chun et al.
5 citations
Aging Cell
Genetics, Aging, and Longevity in Model Organisms
4.77
article

Phosphorylation of an RNA‐Binding Protein Rck/Me31b by Hippo Is Essential for Adipose Tissue Aging

Eunbyul Yeom, Eun‐Soo Kwon, Jason S. Pierce, Yoo Lim Chun, Besim Öğretmen, Je‐Hyun Yoon, Yong Sun Lee, J. Ross Buchan, Kyung‐Won Min, Jeong Ho Chang, L. Ashley Cowart, Jason N. Pitt, Kyoung‐Min Choi, Kwang‐Pyo Lee, H. R. Kim, Kyu‐Sun Lee, Seo Young Yang, Jung‐Hyun Cho, Johana M. Lambert, Jinhwan Lim, Seung‐Jin Kim, Hyejin Mun, Chang Hoon Shin, Matt Kaeberlein, Seungbeom Ko, Sung‐Ung Kang, Yoon-su Ha
article en
5 citations

Abstract

The metazoan lifespan is determined in part by a complex signaling network that regulates energy metabolism and stress responses. Key signaling hubs in this network include insulin/IGF-1, AMPK, mTOR, and sirtuins. The Hippo/Mammalian Ste20-like Kinase1 (MST1) pathway has been reported to maintain lifespan in Caenorhabditis elegans, but its role has not been studied in higher metazoans. In this study, we report that overexpression of Hpo, the MST1 homolog in Drosophila melanogaster, decreased lifespan with concomitant changes in lipid metabolism and aging-associated gene expression, while RNAi Hpo depletion increased lifespan. These effects were mediated primarily by Hpo-induced transcriptional activation of the RNA-binding protein maternal expression at 31B (Me31b)/RCK, resulting in stabilization of mRNA-encoding a lipolytic hormone, Akh. In mouse adipocytes, Hpo/Mst1 mediated adipocyte differentiation, phosphorylation of RNA-binding proteins such as Rck, decapping MRNA 2 (Dcp2), enhancer Of MRNA decapping 3 (Edc3), nucleolin (NCL), and glucagon mRNA stability by interacting with Rck. Decreased lifespan in Hpo-overexpressing Drosophila lines required expression of Me31b, but not DCP2, which was potentially mediated by recovering expression of lipid metabolic genes and formation of lipid droplets. Taken together, our findings suggest that Hpo/Mst1 plays a conserved role in longevity by regulating adipogenesis and fatty acid metabolism.

Aging CellVol. 24(6)
Gangneung–Wonju National University (KR), University of Arizona (US), Johns Hopkins University (US), Medical University of South Carolina (US), Kangwon National University (KR), Virginia Commonwealth University (US), University of Washington (US), University of California, Irvine (US), Johns Hopkins Medicine (US), Hunter Holmes McGuire VA Medical Center (US), Kyungpook National University (KR), MUSC Hollings Cancer Center (US), National Cancer Center (KR), Korea Research Institute of Bioscience and Biotechnology (KR), Sungkyunkwan University (KR), University of Oklahoma (US)
Medical University of South Carolina, University of Oklahoma, Department of Veterans' Affairs, Australian Government, Ministry of Education, Ministry of Trade, Industry and Energy, National Research Foundation of Korea, Ministry of Science and ICT, South Korea, National Institutes of Health, National Institute of Neurological Disorders and Stroke
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Genetics, Aging, and Longevity in Model Organisms
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