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A mouse model for functional dissection of TAB1 O-GlcNAcylation
Florence Authier1, Villő Muha1, Daan M F van Aalten1
1Division of Gene Regulation and Expression, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
Abstract:
Background: O-GlcNAcylation is a posttranslational modification associated with various physiological and pathophysiological processes including diabetes, cancer, neurodegeneration and inflammation. However, the biological mechanisms underlying the role of specific O-GlcNAc sites and their link to phenotypes remain largely unexplored due to lack of suitable in vivo models. TGF-β activated kinase-1 binding protein-1 (TAB1) is a scaffolding protein required for TGF-β activated kinase-1 (TAK1) mediated signalling. A single O-GlcNAc site has been identified on human TAB1 that modulates TAK1-mediated cytokine release in cells. Methods: Here, we report the generation of the Tab1 mouse model using a constitutive knock-in strategy. The Tab1 mice carry a Ser393Ala (S393A) mutation that leads to loss of O-GlcNAcylation site on TAB1. Results: We did not observe any obvious phenotype in Tab1 mice. Loss of O-GlcNAcylation on TAB1 has no consequences on TAB1 protein level or on TAB1-TAK1 interaction. Conclusions: The homozygous Tab1 mice are viable and develop with no obvious abnormalities, providing a powerful tool to further investigate the role of O-GlcNAc on TAB1 in the inflammatory response in the context of a whole organism.
Insights
Mice lacking O-GlcNAcylation on TAB1 protein (TGF-β activated kinase-1 binding protein-1) show no obvious abnormalities. This new mouse model is crucial for studying O-GlcNAcylation
Area of Science:
- Biochemistry
- Molecular Biology
- Immunology
Background:
- O-GlcNAcylation is a critical posttranslational modification impacting numerous cellular processes.
- Understanding specific O-GlcNAc sites and their physiological roles is limited by a lack of appropriate in vivo models.
- TAB1 (TGF-β activated kinase-1 binding protein-1) has a known O-GlcNAc site influencing cytokine release via TAK1 signaling.
Purpose of the Study:
- To generate and characterize a mouse model lacking O-GlcNAcylation on TAB1.
- To investigate the in vivo consequences of losing the TAB1 O-GlcNAc modification.
- To establish a tool for studying TAB1 O-GlcNAcylation in inflammatory responses.
Main Methods:
- Generation of a constitutive knock-in mouse model (Tab1 S393A).
- The mutation ablates the single identified O-GlcNAcylation site on TAB1.
- Phenotypic analysis of Tab1 mutant mice.
Main Results:
- Tab1 mutant mice are viable and exhibit no overt phenotypic abnormalities.
- Loss of TAB1 O-GlcNAcylation does not affect TAB1 protein levels.
- The interaction between TAB1 and TAK1 remains unaffected by the mutation.
Conclusions:
- Homozygous Tab1 mutant mice are healthy, demonstrating the viability of ablating this specific O-GlcNAc site.
- This mouse model provides a valuable resource for dissecting the in vivo role of TAB1 O-GlcNAcylation in biological processes, particularly inflammation.
- Further research can now explore the nuanced functions of TAB1 O-GlcNAcylation within a whole organism context.
