Abstract

Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases.

Hyperammonemia occurs in liver diseases affecting ureagenesis, and is life-threatening. Here, the authors show that liver UDP-GlcNAc is increased during hyperammonemia, leading to O-GlcNAcylation of the rate-limiting ureagenesis enzyme CPS1, that enhanced ureagenesis and ammonia detoxification. They also showed that pharmacological increase of protein O-GlcNAcylation reduces hyperammonemia in mouse models of liver disease.

Details

Title
O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Author
Soria, Leandro R. 1   VIAFID ORCID Logo  ; Makris, Georgios 2 ; D’Alessio, Alfonso M. 1 ; De Angelis, Angela 1 ; Boffa, Iolanda 1 ; Pravata, Veronica M. 3   VIAFID ORCID Logo  ; Rüfenacht, Véronique 2 ; Attanasio, Sergio 1 ; Nusco, Edoardo 1 ; Arena, Paola 1   VIAFID ORCID Logo  ; Ferenbach, Andrew T. 3 ; Paris, Debora 4 ; Cuomo, Paola 4 ; Motta, Andrea 4   VIAFID ORCID Logo  ; Nitzahn, Matthew 5 ; Lipshutz, Gerald S. 6   VIAFID ORCID Logo  ; Martínez-Pizarro, Ainhoa 7 ; Richard, Eva 7   VIAFID ORCID Logo  ; Desviat, Lourdes R. 7   VIAFID ORCID Logo  ; Häberle, Johannes 2   VIAFID ORCID Logo  ; van Aalten, Daan M. F. 3   VIAFID ORCID Logo  ; Brunetti-Pierri, Nicola 8   VIAFID ORCID Logo 

 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy (GRID:grid.410439.b) (ISNI:0000 0004 1758 1171) 
 University Children’s Hospital, Division of Metabolism and Children’s Research Center, Zurich, Switzerland (GRID:grid.412341.1) (ISNI:0000 0001 0726 4330) 
 University of Dundee, School of Life Sciences, Dundee, UK (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876) 
 National Research Council, Institute of Biomolecular Chemistry, Pozzuoli, Italy (GRID:grid.5326.2) (ISNI:0000 0001 1940 4177) 
 David Geffen School of Medicine at UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
 David Geffen School of Medicine at UCLA, Molecular Biology Institute, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718); David Geffen School of Medicine at UCLA, Surgery, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
 Universidad Autónoma, Centro de Biología Molecular Severo Ochoa UAM-CSIC, CIBERER, IdiPaz, Madrid, Spain (GRID:grid.5515.4) (ISNI:0000000119578126) 
 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy (GRID:grid.410439.b) (ISNI:0000 0004 1758 1171); Federico II University, Department of Translational Medicine, Naples, Italy (GRID:grid.4691.a) (ISNI:0000 0001 0790 385X); University of Naples Federico II, Scuola Superiore Meridionale (SSM, School of Advanced Studies), Genomics and Experimental Medicine Program, Naples, Italy (GRID:grid.4691.a) (ISNI:0000 0001 0790 385X) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2709801941
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.