Abstract
Glycophagy, a selective form of autophagy critical for glycogen homeostasis, relies on the glycogen cargo receptor called starch-binding domain-containing protein 1 (STBD1), yet its evolutionary origins remain elusive. Here, we provide evidence that the Pacific oyster Crassostrea gigas utilizes glycophagy to manage glycogen mobilization during periods of energy deprivation. We identify an oyster STBD1 protein, and trace its origins through phylogenetic and comparative genomic analysis of the carbohydrate binding module family 20 (CBM20) domain within this protein across metazoans. Oyster STBD1 and those in other invertebrates contain an N-terminal CBM20, contrasting the C-terminal location of CBM20 in vertebrate STBD1. N-terminal CBM20 STBD1 proteins have a deep origin in bilaterians, with the vertebrate structural arrangement arising at the chordate root. Structural modelling and functional studies reveal that the N-terminal organization of the CBM20 domain in STBD1 enhances glycogen binding, with subsequent anchoring by GABARAPL2, facilitating an increased glycogen flux into autophagosomes for lysosomal degradation. We conclude that glycophagy is deeply conserved in bilaterians and that STBD1 structural evolution underlies potentially adaptive variation in metabolic strategies across distinct animal clades.
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Acknowledgements
We acknowledge the support of the High-Performance Biological Supercomputing Center at the Ocean University of China, and the Marine Biodiversity and Evolution Research Institute’s Instrument and Equipment Sharing Platform for providing the high-speed centrifuge (XPN-100) for this research. This work was supported by grants from the National Natural Science Foundation of China (32341060 and 42276112), the Key Research and Development Program of Shandong Province (2021ZLGX03), the National Key Research and Development Program of China (2022YFD2400300), the Fundamental Research Funds for the Central Universities (202461040), and the earmarked fund for the Agriculture Research System of China (CARS-49). DJM received support from an Institute Strategic Programme award (BBS/E/RL/230001 C) from the Biotechnology and Biological Sciences Research Council to The Roslin Institute.
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Liting Ren: Methodology, Investigation, Formal analysis, Data curation, Writing–original draft. Yitian Bai: Investigation, Data curation and Writing–original draft. Chenyu Shi and Zhengwang Hao: Investigation. Qi Li: Supervision and Resources. Daniel J Macqueen: Writing–review & editing, Funding acquisition and Supervision. Shikai Liu: Writing–review & editing, Supervision, Funding acquisition, Formal analysis, Conceptualization.
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Ren, L., Bai, Y., Shi, C. et al. Glycophagy is an ancient bilaterian pathway supporting metabolic adaptation through STBD1 structural evolution. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09546-6
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DOI: https://doi.org/10.1038/s42003-026-09546-6
