Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation
Abstract UDP-GlcNAc serves as a building block for glycosaminoglycan (GAG) chains in cartilage proteoglycans and simultaneously acts as a substrate for O-GlcNAcylation. Here, we show that transporters for UDP-GlcNAc to the endoplasmic reticulum (ER) and Golgi are significantly downregulated in osteo...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-55085-1 |
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| author | Donghyun Kang Jeeyeon Lee Geunho Yook Sehan Jeong Jungkwon Shin Mi-Sung Kim Yi-Jun Kim Hyeryeon Jung Jinsung Ahn Tae Woo Kim Moon Jong Chang Chong Bum Chang Seung-Baik Kang Won Ho Yang Yong-ho Lee Jin Won Cho Eugene C. Yi Chanhee Kang Jin-Hong Kim |
| author_facet | Donghyun Kang Jeeyeon Lee Geunho Yook Sehan Jeong Jungkwon Shin Mi-Sung Kim Yi-Jun Kim Hyeryeon Jung Jinsung Ahn Tae Woo Kim Moon Jong Chang Chong Bum Chang Seung-Baik Kang Won Ho Yang Yong-ho Lee Jin Won Cho Eugene C. Yi Chanhee Kang Jin-Hong Kim |
| author_sort | Donghyun Kang |
| collection | DOAJ |
| description | Abstract UDP-GlcNAc serves as a building block for glycosaminoglycan (GAG) chains in cartilage proteoglycans and simultaneously acts as a substrate for O-GlcNAcylation. Here, we show that transporters for UDP-GlcNAc to the endoplasmic reticulum (ER) and Golgi are significantly downregulated in osteoarthritic cartilage, leading to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. Mechanistically, upregulated O-GlcNAcylation governs the senescence-associated secretory phenotype (SASP) by stabilizing GATA4 via O-GlcNAcylation at S406, which compromises its degradation by p62-mediated selective autophagy. Elevated O-GlcNAcylation in the superficial layer of osteoarthritic cartilage coincides with increased GATA4 levels. The topical deletion of Gata4 in this cartilage layer ameliorates post-traumatic osteoarthritis (OA) in mice while inhibiting O-GlcNAc transferase mitigates OA by decreasing GATA4 levels. Excessive glucosamine-induced O-GlcNAcylation stabilizes GATA4 in chondrocytes and exacerbates post-traumatic OA in mice. Our findings elucidate the role of UDP-GlcNAc compartmentalization in regulating secretory pathways associated with chronic joint inflammation, providing a senostatic strategy for the treatment of OA. |
| format | Article |
| id | doaj-art-06bf9c03dbf44a3d895097273164a3ca |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-06bf9c03dbf44a3d895097273164a3ca2025-02-09T12:43:59ZengNature PortfolioNature Communications2041-17232025-02-0116111910.1038/s41467-024-55085-1Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylationDonghyun Kang0Jeeyeon Lee1Geunho Yook2Sehan Jeong3Jungkwon Shin4Mi-Sung Kim5Yi-Jun Kim6Hyeryeon Jung7Jinsung Ahn8Tae Woo Kim9Moon Jong Chang10Chong Bum Chang11Seung-Baik Kang12Won Ho Yang13Yong-ho Lee14Jin Won Cho15Eugene C. Yi16Chanhee Kang17Jin-Hong Kim18Department of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Environmental Medicine, College of Medicine, Ewha Womans UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology, College of Medicine, Seoul National UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology, College of Medicine, Seoul National UniversityDepartment of Orthopaedic Surgery, Seoul National University Boramae HospitalDepartment of Orthopaedic Surgery, Seoul National University Boramae HospitalDepartment of Orthopaedic Surgery, Seoul National University Bundang HospitalDepartment of Orthopaedic Surgery, Seoul National University Boramae HospitalDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei UniversityGlycosylation Network Research Center, Yonsei UniversityDepartment of Systems Biology, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Molecular Medicine and Biopharmaceutical Sciences, School of Convergence Science and Technology, College of Medicine, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityDepartment of Biological Sciences, College of Natural Sciences, Seoul National UniversityAbstract UDP-GlcNAc serves as a building block for glycosaminoglycan (GAG) chains in cartilage proteoglycans and simultaneously acts as a substrate for O-GlcNAcylation. Here, we show that transporters for UDP-GlcNAc to the endoplasmic reticulum (ER) and Golgi are significantly downregulated in osteoarthritic cartilage, leading to increased cytosolic UDP-GlcNAc and O-GlcNAcylation in chondrocytes. Mechanistically, upregulated O-GlcNAcylation governs the senescence-associated secretory phenotype (SASP) by stabilizing GATA4 via O-GlcNAcylation at S406, which compromises its degradation by p62-mediated selective autophagy. Elevated O-GlcNAcylation in the superficial layer of osteoarthritic cartilage coincides with increased GATA4 levels. The topical deletion of Gata4 in this cartilage layer ameliorates post-traumatic osteoarthritis (OA) in mice while inhibiting O-GlcNAc transferase mitigates OA by decreasing GATA4 levels. Excessive glucosamine-induced O-GlcNAcylation stabilizes GATA4 in chondrocytes and exacerbates post-traumatic OA in mice. Our findings elucidate the role of UDP-GlcNAc compartmentalization in regulating secretory pathways associated with chronic joint inflammation, providing a senostatic strategy for the treatment of OA.https://doi.org/10.1038/s41467-024-55085-1 |
| spellingShingle | Donghyun Kang Jeeyeon Lee Geunho Yook Sehan Jeong Jungkwon Shin Mi-Sung Kim Yi-Jun Kim Hyeryeon Jung Jinsung Ahn Tae Woo Kim Moon Jong Chang Chong Bum Chang Seung-Baik Kang Won Ho Yang Yong-ho Lee Jin Won Cho Eugene C. Yi Chanhee Kang Jin-Hong Kim Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation Nature Communications |
| title | Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation |
| title_full | Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation |
| title_fullStr | Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation |
| title_full_unstemmed | Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation |
| title_short | Regulation of senescence-associated secretory phenotypes in osteoarthritis by cytosolic UDP-GlcNAc retention and O-GlcNAcylation |
| title_sort | regulation of senescence associated secretory phenotypes in osteoarthritis by cytosolic udp glcnac retention and o glcnacylation |
| url | https://doi.org/10.1038/s41467-024-55085-1 |
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