O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Leandro R. Soria; Georgios Makris; Alfonso M. D'Alessio; Angela De Angelis; Iolanda Boffa; Veronica M. Pravata; Véronique Rüfenacht; Sergio Attanasio; Edoardo Nusco; Paola Arena; Andrew T. Ferenbach; Debora Paris; Paola Cuomo; Andrea Motta; Matthew Nitzahn; Gerald S. Lipshutz; Ainhoa Martínez-Pizarro; Eva Richard; Lourdes R. Desviat; Johannes Häberle; Daan M. F. van Aalten; Nicola Brunetti-Pierri

doi:10.1038/s41467-022-32904-x

O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Leandro R. Soria (Lead / Corresponding author)
, Georgios Makris
, Alfonso M. D'Alessio
, Angela De Angelis
, Iolanda Boffa
, Veronica M. Pravata
, Véronique Rüfenacht
, Sergio Attanasio
, Edoardo Nusco
, Paola Arena
, Andrew T. Ferenbach
, Debora Paris
, Paola Cuomo
, Andrea Motta
, Matthew Nitzahn
, Gerald S. Lipshutz
, Ainhoa Martínez-Pizarro
, Eva Richard
, Lourdes R. Desviat
, Johannes Häberle

Daan M. F. van Aalten, Nicola Brunetti-Pierri (Lead / Corresponding author)

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

205 Downloads (Pure)

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.

Original language	English
Article number	5212
Number of pages	14
Journal	Nature Communications
Volume	13
DOIs	https://doi.org/10.1038/s41467-022-32904-x
Publication status	Published - 5 Sept 2022

Keywords

Acetylglucosamine
Ammonia/metabolism
Animals
Carbamoyl-Phosphate Synthase (Ammonia)/genetics
Disease Models, Animal
Hyperammonemia/genetics
Mammals/metabolism
Mice
N-Acetylglucosaminyltransferases/genetics
Propionic Acidemia
Protein Processing, Post-Translational
Urea/metabolism
Uridine Diphosphate/metabolism

ASJC Scopus subject areas

General
General Physics and Astronomy
General Chemistry
General Biochemistry,Genetics and Molecular Biology

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10.1038/s41467-022-32904-xLicence: CC BY

Final published versionFinal published version, 1.8 MBLicence: CC BY

Cite this

Soria, L. R., Makris, G., D'Alessio, A. M., De Angelis, A., Boffa, I., Pravata, V. M., Rüfenacht, V., Attanasio, S., Nusco, E., Arena, P., Ferenbach, A. T., Paris, D., Cuomo, P., Motta, A., Nitzahn, M., Lipshutz, G. S., Martínez-Pizarro, A., Richard, E., Desviat, L. R., ... Brunetti-Pierri, N. (2022). O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis. Nature Communications, 13, Article 5212. https://doi.org/10.1038/s41467-022-32904-x

@article{06deeb8db27344dc90652e5e2a416baa,

title = "O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis",

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.",

keywords = "Acetylglucosamine, Ammonia/metabolism, Animals, Carbamoyl-Phosphate Synthase (Ammonia)/genetics, Disease Models, Animal, Hyperammonemia/genetics, Mammals/metabolism, Mice, N-Acetylglucosaminyltransferases/genetics, Propionic Acidemia, Protein Processing, Post-Translational, Urea/metabolism, Uridine Diphosphate/metabolism",

author = "Soria, \{Leandro R.\} and Georgios Makris and D'Alessio, \{Alfonso M.\} and \{De Angelis\}, Angela and Iolanda Boffa and Pravata, \{Veronica M.\} and V{\'e}ronique R{\"u}fenacht and Sergio Attanasio and Edoardo Nusco and Paola Arena and Ferenbach, \{Andrew T.\} and Debora Paris and Paola Cuomo and Andrea Motta and Matthew Nitzahn and Lipshutz, \{Gerald S.\} and Ainhoa Mart{\'i}nez-Pizarro and Eva Richard and Desviat, \{Lourdes R.\} and Johannes H{\"a}berle and \{van Aalten\}, \{Daan M. F.\} and Nicola Brunetti-Pierri",

note = "Funding Information: This work was supported by grants of Fondazione Telethon Italy (to N.B.‐P.), MIUR (PRIN2017 to N.B.‐P.), of the Swiss National Science Foundation (grant 320030\_176088 to J.H.), of the US National Institutes of Health grants (R21NS091654 and R01NS100979 both to G.S.L.), of the Spanish Ministry of Science and Innovation (PID2019-105344RB-I00/AEI/10.13039/501100011033 to L.R.D. and E.R.), and by a Wellcome Trust Investigator Award (110061 to D.M.F.v.A.). {\textcopyright} 2022. The Author(s).",

year = "2022",

month = sep,

day = "5",

doi = "10.1038/s41467-022-32904-x",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

}

Soria, LR, Makris, G, D'Alessio, AM, De Angelis, A, Boffa, I, Pravata, VM, Rüfenacht, V, Attanasio, S, Nusco, E, Arena, P, Ferenbach, AT, Paris, D, Cuomo, P, Motta, A, Nitzahn, M, Lipshutz, GS, Martínez-Pizarro, A, Richard, E, Desviat, LR, Häberle, J, van Aalten, DMF & Brunetti-Pierri, N 2022, 'O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis', Nature Communications, vol. 13, 5212. https://doi.org/10.1038/s41467-022-32904-x

TY - JOUR

T1 - O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

AU - Soria, Leandro R.

AU - Makris, Georgios

AU - D'Alessio, Alfonso M.

AU - De Angelis, Angela

AU - Boffa, Iolanda

AU - Pravata, Veronica M.

AU - Rüfenacht, Véronique

AU - Attanasio, Sergio

AU - Nusco, Edoardo

AU - Arena, Paola

AU - Ferenbach, Andrew T.

AU - Paris, Debora

AU - Cuomo, Paola

AU - Motta, Andrea

AU - Nitzahn, Matthew

AU - Lipshutz, Gerald S.

AU - Martínez-Pizarro, Ainhoa

AU - Richard, Eva

AU - Desviat, Lourdes R.

AU - Häberle, Johannes

AU - van Aalten, Daan M. F.

AU - Brunetti-Pierri, Nicola

N1 - Funding Information: This work was supported by grants of Fondazione Telethon Italy (to N.B.‐P.), MIUR (PRIN2017 to N.B.‐P.), of the Swiss National Science Foundation (grant 320030_176088 to J.H.), of the US National Institutes of Health grants (R21NS091654 and R01NS100979 both to G.S.L.), of the Spanish Ministry of Science and Innovation (PID2019-105344RB-I00/AEI/10.13039/501100011033 to L.R.D. and E.R.), and by a Wellcome Trust Investigator Award (110061 to D.M.F.v.A.). © 2022. The Author(s).

PY - 2022/9/5

Y1 - 2022/9/5

N2 - 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.

AB - 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.

KW - Acetylglucosamine

KW - Ammonia/metabolism

KW - Animals

KW - Carbamoyl-Phosphate Synthase (Ammonia)/genetics

KW - Disease Models, Animal

KW - Hyperammonemia/genetics

KW - Mammals/metabolism

KW - Mice

KW - N-Acetylglucosaminyltransferases/genetics

KW - Propionic Acidemia

KW - Protein Processing, Post-Translational

KW - Urea/metabolism

KW - Uridine Diphosphate/metabolism

UR - https://www.scopus.com/pages/publications/85137209674

U2 - 10.1038/s41467-022-32904-x

DO - 10.1038/s41467-022-32904-x

M3 - Article

C2 - 36064721

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

M1 - 5212

ER -

O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Abstract

Keywords

ASJC Scopus subject areas

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Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

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O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

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Molecular Mechanisms of O-GICNAC Signalling (Investigator award)

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