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Immunity. 2019 Mar 19;50(3):576-590.e6. doi: 10.1016/j.immuni.2019.01.007. Epub 2019 Feb 12.

O-GlcNAc Transferase Suppresses Inflammation and Necroptosis by Targeting Receptor-Interacting Serine/Threonine-Protein Kinase 3.

Author information

1
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
2
Department of Hepatobiliary Surgery and Liver Transplantation, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, China.
3
Department of Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, Shandong, China.
4
Eppley Institute for Research in Cancer and Allied Diseases, Nebraska Medical Center, Omaha, NE 68198, USA.
5
Department of Internal Medicine, Division of infectious Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA.
6
Department of Chemistry, Nebraska Center for Integrated Biomolecular Communication, University of Nebraska-Lincoln, Lincoln, NE 68588, USA.
7
Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
8
Proteomics Core Facility, Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
9
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
10
Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48105, USA.
11
Program in Integrative Cell Signaling and Neurobiology of Metabolism, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
12
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
13
Department of Microbial Infection and Immunity, Infectious Disease Institute, The Ohio State University Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA. Electronic address: haitao.wen@osumc.edu.

Abstract

Elevated glucose metabolism in immune cells represents a hallmark feature of many inflammatory diseases, such as sepsis. However, the role of individual glucose metabolic pathways during immune cell activation and inflammation remains incompletely understood. Here, we demonstrate a previously unrecognized anti-inflammatory function of the O-linked β-N-acetylglucosamine (O-GlcNAc) signaling associated with the hexosamine biosynthesis pathway (HBP). Despite elevated activities of glycolysis and the pentose phosphate pathway, activation of macrophages with lipopolysaccharide (LPS) resulted in attenuated HBP activity and protein O-GlcNAcylation. Deletion of O-GlcNAc transferase (OGT), a key enzyme for protein O-GlcNAcylation, led to enhanced innate immune activation and exacerbated septic inflammation. Mechanistically, OGT-mediated O-GlcNAcylation of the serine-threonine kinase RIPK3 on threonine 467 (T467) prevented RIPK3-RIPK1 hetero- and RIPK3-RIPK3 homo-interaction and inhibited downstream innate immunity and necroptosis signaling. Thus, our study identifies an immuno-metabolic crosstalk essential for fine-tuning innate immune cell activation and highlights the importance of glucose metabolism in septic inflammation.

KEYWORDS:

HBP; O-GlcNAc; OGT; RIPK3; inflammation; necroptosis

Comment in

PMID:
30770249
PMCID:
PMC6426684
[Available on 2020-03-19]
DOI:
10.1016/j.immuni.2019.01.007

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