Peer-reviewedCC BY-NCScience Advances
S -Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders
19 affiliations
- 1Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
- 2Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, 80134 Naples, Italy.
- 3Medical Genetics Unit, AORN Santobono-Pausilipon—IRCCS, 80122 Naples, Italy.
- 4Department of Pharmacology and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
- 5Oral and Maxillofacial Anatomy, Tokushima University Graduate School, Tokushima 770-8504, Japan.
- 6Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
- 7Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
- 8International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
- 9Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy.
- 10Université Claude Bernard Lyon 1, INSERM UMR-S1213, Lyon 69008, France.
- 11Université Paris-Saclay, Université Évry, Inserm, Genethon, Integrare research unit UMR_S951, Evry 91000, France.
- 12Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
- 13Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark.
- 14Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
- 15Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
- 16Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA.
- 17Research Unit of Complex Traits, Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy.
- 18Bambino Gesù Children’s Hospital, IRCCS, 00146 Rome, Italy.
- 19Institute for Transformative Molecular Medicine and Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
Abstract
Nuclear glycogen storage has been known for nearly 100 years. However, its role in diseases remains unclear. Here, we found nuclear glycogen storage in livers of mice and humans with argininosuccinic aciduria (ASA), an inborn error of metabolism. Nuclear glycogenolysis sustains histone acetylation and liver homeostasis. We show that hepatic nuclear glycogenolysis is regulated by nitric oxide (NO)–dependent control of the nuclear abundance of liver glycogen phosphorylase (PYGL), an enzyme involved in glycogen breakdown that translocates from the cytosol to the nucleus. In vivo, NO supplementation restored the nuclear content of PYGL by promoting its S -nitrosylation at cysteine-446 and its nuclear translocation. Next, we found that nuclear import of PYGL is mediated by HNRNPF, a regulator of RNA maturation that shuttles between the nucleus and cytosol, thus linking control of gene expression to RNA metabolism. Similar changes were detected in both rodent and human livers with metabolic dysfunction-associated steatotic liver disease (MASLD), a global health concern with limited therapies, that shares with ASA a decrease in NO synthesis. In conclusion, our findings reveal a mechanism underlying reduced glycogenolysis and hepatic nuclear glycogen storage disorders, a new group of metabolic disorders.
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BibTeX
@article{soria2026nitrosylation,
title = {{S -Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders}},
author = {Leandro R. Soria and Alfonso M. D’Alessio and Vincenzo Casertano and Elena Polishchuk and Andrea Pasquadibisceglie and Iolanda Boffa and Anna Diana and Rossella De Cegli and Lucia De Stefano and Edoardo Nusco and Paola Arena and Matteo Audano and Nico Mitro and Tsuyoshi Morita and Otto Baba and Antonietta Tarallo and Giancarlo Parenti and Sonam Gurung and Dany P. Perocheau and Davide Selvestrel and Giovanni Sorrentino and Fabienne Rajas and Giuseppe Ronzitti and Andrés F. Muro and Ayelet Erez and Karen Louise Thomsen and Pankaj K. Singh and Charles John Arends and Maria Rita Braghini and Samira Safarikia and Joseph C. Schindler and Julien Baruteau and Young Mok Lee and Anna Alisi and Marco Spada and Carlo Dionisi-Vici and Jonathan S. Stamler and Matthew S. Gentry and Nicola Brunetti-Pierri},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aej6157},
url = {https://www.science.org/doi/10.1126/sciadv.aej6157},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - S -Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders
AU - Leandro R. Soria
AU - Alfonso M. D’Alessio
AU - Vincenzo Casertano
AU - Elena Polishchuk
AU - Andrea Pasquadibisceglie
AU - Iolanda Boffa
AU - Anna Diana
AU - Rossella De Cegli
AU - Lucia De Stefano
AU - Edoardo Nusco
AU - Paola Arena
AU - Matteo Audano
AU - Nico Mitro
AU - Tsuyoshi Morita
AU - Otto Baba
AU - Antonietta Tarallo
AU - Giancarlo Parenti
AU - Sonam Gurung
AU - Dany P. Perocheau
AU - Davide Selvestrel
AU - Giovanni Sorrentino
AU - Fabienne Rajas
AU - Giuseppe Ronzitti
AU - Andrés F. Muro
AU - Ayelet Erez
AU - Karen Louise Thomsen
AU - Pankaj K. Singh
AU - Charles John Arends
AU - Maria Rita Braghini
AU - Samira Safarikia
AU - Joseph C. Schindler
AU - Julien Baruteau
AU - Young Mok Lee
AU - Anna Alisi
AU - Marco Spada
AU - Carlo Dionisi-Vici
AU - Jonathan S. Stamler
AU - Matthew S. Gentry
AU - Nicola Brunetti-Pierri
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aej6157
UR - https://www.science.org/doi/10.1126/sciadv.aej6157
AB - Nuclear glycogen storage has been known for nearly 100 years. However, its role in diseases remains unclear. Here, we found nuclear glycogen storage in livers of mice and humans with argininosuccinic aciduria (ASA), an inborn error of metabolism. Nuclear glycogenolysis sustains histone acetylation and liver homeostasis. We show that hepatic nuclear glycogenolysis is regulated by nitric oxide (NO)–dependent control of the nuclear abundance of liver glycogen phosphorylase (PYGL), an enzyme involved in glycogen breakdown that translocates from the cytosol to the nucleus. In vivo, NO supplementation restored the nuclear content of PYGL by promoting its S -nitrosylation at cysteine-446 and its nuclear translocation. Next, we found that nuclear import of PYGL is mediated by HNRNPF, a regulator of RNA maturation that shuttles between the nucleus and cytosol, thus linking control of gene expression to RNA metabolism. Similar changes were detected in both rodent and human livers with metabolic dysfunction-associated steatotic liver disease (MASLD), a global health concern with limited therapies, that shares with ASA a decrease in NO synthesis. In conclusion, our findings reveal a mechanism underlying reduced glycogenolysis and hepatic nuclear glycogen storage disorders, a new group of metabolic disorders.
SN - 2375-2548
ER -