Human glycogenins maintain glucose homeostasis by regulating glycogen metabolism
Proper regulation of glycogen metabolism is fundamental to cellular energy homeostasis, and its disruption is associated with various metabolic disorders, including glycogen storage diseases (GSDs) and potentially diabetes. Despite glycogen's role as an essential energy reservoir, the mechanisms governing its synthesis and structural diversity across tissues remain unclear. Here, we uncover the distinct physiological roles of the human glycogenins GYG1 and GYG2 in glycogen synthesis. Through cellular models, structural biology, and biochemical analyses, we demonstrate that, unlike GYG1, GYG2 exhibits minimal autoglycosylation activity and acts as a suppressor of glycogen formation. Together, these two glycogenins coordinate glycogen synthase activity and influence glycogen assembly in a cell-type-dependent manner. Importantly, these glycogenins modulate glucose metabolic pathways, thereby ensuring cellular glucose homeostasis. These findings address longstanding questions in glycogen metabolism and establish both GYG1 and GYG2 as critical regulators of glycogen synthesis and breakdown in human, providing insights with potential therapeutic implications for treating GSDs and metabolic diseases.
Authors
- Yu‐Ting Tseng (ORCID: https://orcid.org/0000-0001-7803-4970)
- Carmay Lim (ORCID: https://orcid.org/0000-0001-9077-7769)
- Yanxing Chen (ORCID: https://orcid.org/0000-0001-6346-9752)
- Yu-Chung Pien (ORCID: https://orcid.org/0000-0001-6028-2044)
- Hsin‐Yung Yen (ORCID: https://orcid.org/0000-0002-6612-3324)
- Chung‐Cheng Chen (ORCID: https://orcid.org/0000-0003-1114-0255)
- Ying-Ting Lee
- Sung‐Jan Lin (ORCID: https://orcid.org/0000-0003-1325-3464)
- Tzu‐Han Weng
- Tzu-Han Hsu (ORCID: https://orcid.org/0000-0002-6277-2765)
- Su‐Yi Tsai (ORCID: https://orcid.org/0000-0002-7423-645X)
- Kuo‐Chiang Hsia (ORCID: https://orcid.org/0000-0002-4409-6732)
- Po-Pang Chen (ORCID: https://orcid.org/0009-0001-8533-301X)
- Ching-Jou Chen
- Yian Chen (ORCID: https://orcid.org/0000-0002-7310-5159)
- Wen-Po Hsiao
Institutions
- National Taiwan University of Science and Technology (TW)
- National Taiwan University (TW)
- Institute of Biological Chemistry, Academia Sinica (TW)
- Institute of Biomedical Sciences, Academia Sinica (TW)
- National Taiwan University Hospital (TW)
- Institute of Molecular Biology, Academia Sinica (TW)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-07-16
- DOI
- https://doi.org/10.1038/s41467-025-61862-3
- Citations
- 3
- Primary Topic
- Glycogen Storage Diseases and Myoclonus
- Type
- article
- Field-Weighted Citation Impact
- 5.00
Funders
- University of Leeds
- Academia Sinica
- National Taiwan University
- National Science and Technology Council
- Genomics Research Center, Academia Sinica