O-GlcNAc cycling: implications for neurodegenerative disorders - PubMed (original) (raw)

Review

O-GlcNAc cycling: implications for neurodegenerative disorders

Brooke D Lazarus et al. Int J Biochem Cell Biol. 2009 Nov.

Abstract

The dynamic post-translational modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc), termed O-GlcNAcylation, is an important mechanism for modulating cellular signaling pathways. O-GlcNAcylation impacts transcription, translation, organelle trafficking, proteasomal degradation and apoptosis. O-GlcNAcylation has been implicated in the etiology of several human diseases including type-2 diabetes and neurodegeneration. This review describes the pair of enzymes responsible for the cycling of this post-translational modification: O-GlcNAc transferase (OGT) and beta-N-acetylglucosaminidase (OGA), with a focus on the function of their structural domains. We will also highlight the important processes and substrates regulated by these enzymes, with an emphasis on the role of O-GlcNAc as a nutrient sensor impacting insulin signaling and the cellular stress response. Finally, we will focus attention on the many ways by which O-GlcNAc cycling may affect the cellular machinery in the neuroendocrine and central nervous systems.

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Figures

Fig. 1

Fig. 1. The ‘O-GlcNAc code’

In this review, we will highlight the roles of the nutrient sensing hexosamine biosynthetic pathway to generate UDP-GlcNAc, the precursor to O-GlcNAc (lower left). The enzymes of O-GlcNAc cycling, O-GlcNAc transferase and O-GlcNAcase (upper left) are differentially targeted and by interacting with adapter molecules (Trak1, HAP etc.), mediate the dynamic O-GlcNAc modification of key cellular substrates shown in the lower right.

Fig 2

Fig 2. Structure and function of OGA isoforms

The two main isoforms of O-GlcNAcase (long OGA and short OGA) contain a catalytic domain (blue) and the N-terminus that belongs to the family 84 of glycoside hydrolases. A crystal structure from Clostridium perfringens with PUGNAc in the active site is shown. Long OGA also contains a histone acetyltransferase domain at the C- terminus that is lacking in short OGA. The HAT domain from the PDB structure GCN5 is shown in green for illustrative purposes. Short OGA contains a unique 15 amino acid tail (yellow).

Fig 3

Fig 3. Structure and function of OGT isoforms

OGT is expressed as three main isoforms with varying numbers of tetratricopeptide repeat domains (TPR, purple). These differentially targeted isoforms all contain an identical catalytic domain (red) that is interrupted by a linker domain (gray). A phosphatidylinositide 3,4,5-triphosphate targeting domain (PPO) is found in all isoforms and directs the enzyme to the plasma membrane following PI-3 Kinase activation. mOGT contains a unique mitochondrial targeting sequence (MTS) that directs this isoform to the mitochondria. B. A composite of the TPR (purple) and catalytic domain (red) based upon the PDB files (1W3B and 2VSN, respectively) is shown. The catalytic domain is in complex with UDP Both monomers of the homodimer are shown in their approximate orientation to each other, with one monomer (lighter opacity) in the horizontal plane and the other (red and purple) presented in the vertical plane. The PPO domain on the outer surface of the catalytic domain is illustrated in both monomers.

Fig 4

Fig 4. O-GlcNAc cycling and neurodegeneration: A panoply of possible mechanisms

OGT acts on numerous intracellular targets with established roles in neuronal function and the protection against proteotoxicity. Clockwise from the upper left, OGT modifies Tau and alters its phosphorylation suggesting an influence on Tau aggregation. OGT influences numerous kinase cascades including those of insulin and MAP kinase signaling which could impact the cellular response to stress. O-GlcNAc impacts the transcriptional and translational machinery by decorating chromatin and playing a key role in the formation of stress granules involved in mRNA triage. OGT is also an endogenous inhibitor of the proteasome, limiting proteasomal degradation in response to nutrient flux. Finally, OGT and its adapter molecules such as Trak1 and Trak2 (and possibly Hap) may play a key role in the organelle trafficking and axonal transport critical for neuronal function. Many of these processes are known to be dysregulated in neurodegenerative diseases such as the tauopathies and Alzheimer’s disease.

Fig 5

Fig 5. Axonal movement of mitochondria and neurosecretory vesicles: possible involvement of O-GlcNAc transferase

OGT and organelle transport. OGT binds to the coil-coil domain of the organelle adapter GRIF1 and may regulate the interaction of this adapter with kinesin motors. This complex is tethered to mitochondria by the protein Miro. This association could allow for modulation of the trafficking of mitochondria in response to nutrient flux. Hap1 shares the same coil-coil domain; OGT could interact with Hap1 through this region and regulate synaptic vesicle movement in a similar mechanism.

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