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Publications

Journal Article Ppublish

PubMed: 42826186 DOI: 10.1126/sciadv.aej6157

S-Nitrosylation of glycogen phosphorylase regulates nuclear glycogenolysis and is impaired in metabolic liver disorders.

Sci Adv 12(40):eaej6157

Authors: Leandro R Soria, Alfonso M D'Alessio, Vincenzo Casertano, Elena Polishchuk, Andrea Pasquadibisceglie, Iolanda Boffa, Anna Diana, Rossella De Cegli, Lucia De Stefano, Edoardo Nusco, Paola Arena, Matteo Audano, Nico Mitro, Tsuyoshi Morita, Otto Baba, Antonietta Tarallo, Giancarlo Parenti, Sonam Gurung, Dany P Perocheau, Davide Selvestrel, Giovanni Sorrentino, Fabienne Rajas, Giuseppe Ronzitti, Andrés F Muro, Ayelet Erez, Karen Louise Thomsen, Pankaj K Singh, Charles John Arends, Maria Rita Braghini, Samira Safarikia, Joseph C Schindler, Julien Baruteau, Young Mok Lee, Anna Alisi, Marco Spada, Carlo Dionisi-Vici, Jonathan S Stamler, Matthew S Gentry, Nicola Brunetti-Pierri

Affiliations

  • Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy.
  • Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, University of Naples Federico II, 80134 Naples, Italy.
  • Medical Genetics Unit, AORN Santobono-Pausilipon-IRCCS, 80122 Naples, Italy.
  • Department of Pharmacology and Biomolecular Sciences, University of Milan, 20133 Milan, Italy.
  • Oral and Maxillofacial Anatomy, Tokushima University Graduate School, Tokushima 770-8504, Japan.
  • Department of Translational Medicine, Federico II University of Naples, 80131 Naples, Italy.
  • Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK.
  • International Centre for Genetic Engineering and Biotechnology (ICGEB), 34149 Trieste, Italy.
  • Department of Medical, Surgical and Health Sciences, University of Trieste, 34127 Trieste, Italy.
  • UniversitĂ© Claude Bernard Lyon 1, INSERM UMR-S1213, Lyon 69008, France.
  • UniversitĂ© Paris-Saclay, UniversitĂ© Évry, Inserm, Genethon, Integrare research unit UMR_S951, Evry 91000, France.
  • Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus N DK-8200, Denmark.
  • Department of Biochemistry and Molecular Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
  • Department of Pediatrics, University of Connecticut School of Medicine, Farmington, CT 06030, USA.
  • Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT 06030, USA.
  • Research Unit of Complex Traits, Bambino GesĂ¹ Children's Hospital, IRCCS, 00146 Rome, Italy.
  • Bambino GesĂ¹ Children's Hospital, IRCCS, 00146 Rome, Italy.
  • Institute 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.

MeSH

Cytosol, Glycogen, Phosphorylases, Liver, Glycogen Phosphorylase