Protein O-GlcNAcylation in Physiology and Disease

  • O-GlcNAc'

In the metabolic regulatory network that consists of multiple tissues and organs, there are two major drivers of coordinated action in response to food availability, temperature variation, circadian "zeigeber", and other environmental cues. The first is hormones secreted by various cells and tissues such as insulin (β cell), leptin (fat), FGF21 (liver), and ghrelin (stomach). These hormones act locally and/or systemically to modulate various metabolic processes. Secondly, nutrients and metabolites such as glucose, amino acids, lipids, and ketone bodies are sensed by cells and tissues to fine tune metabolism. Disruptions in the production and/or sensing of these hormones & nutrients will lead to metabolic dysfunction, such as obesity & diabetes. We are interested to understand how metabolic tissues and organs integrate these hormonal and nutritional cues in order to maintain homeostasis.

Posttranslational modifications (PTMs)

PTMs on proteins is an ideal hub relaying hormonal and nutritional cues to metabolism (Fig. 1). For example, amino acid and AMP/ATP modulate protein phosphorylation through mTOR and AMPK, respectively. Acetyl-CoA is used as a donor for histone acetyltransfease (HAT)-mediated acetylation; on the other hand, NAD+ is important for the activity of the sirtuin family of histone deacetylases. S-adenosyl methionine (SAM) is the substrate for histone methyltransferase (HMT). Meanwhile, hormones regulate both the availability of nutrients/metabolites and the level/activity of PTM enzymes. Collectively, these PTMs control epigenetics, transcription, cell signaling, etc., to regulate metabolism.

O-linked N-Acetylglucosamine (O-GlcNAc)

Thousands of intracellular proteins are modified by a single O-GlcNAc moiety at serine or threonine residues, termed O-GlcNAcylation. Two enzymes mediate the addition and removal of O-GlcNAc: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively (Fig. 2). Evidence from our group and others is emerging that this dynamic and reversible modification is a key regulator of diverse cellular processes including signal transduction, transcription, translation, and proteasomal degradation. Perturbations in protein O-GlcNAcylation are implicated in various human diseases such as obesity, diabetes mellitus, and cancer. 

The donor substrate for O-GlcNAcylation, UDP-GlcNAc is derived from nutrients through the hexosamine biosynthetic pathway (HBP). Because cellular levels of UDP-GlcNAc and O-GlcNAc fluctuate with the availability of glucose, free fatty acids, uridine, and glutamine, O-GlcNAc is proposed to be a metabolic sensor, i.e. a good indicator of the overall metabolic status of the cell. In addition, levels of the expression and activity of O-GlcNAc-cycling enzymes are under the control of various stimuli including nutrient availability, hormonal signaling, and stresses. Currently, we are investigating the molecular mechanisms by which O-GlcNAc signaling integrates environmental cues and internal signals to regulate various physiological processes. 

Related publications:

1. Liu B, Salgado OC, Singh S, Hippen KL, Maynard JC, Burlingame AL, Ball LE, Blazar BR, Farrar MA, Hogquist KA, Ruan HB. (2019). The lineage stability and suppressive program of regulatory T cells require protein O-GlcNAcylation. Nature Comunications. 10:354.
2. Ruan HB, Ma Y, Torres S, Zhang B, Feriod C, Heck RM, Qian K, Fu M, Li X, Nathanson MH, Bennett AM, Nie Y, Ehrlich BE, Yang X. (2017). Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes & Development. 31(16): 1655-1665.
3. Ruan HB, Nie Y, Yang, X. (2013). Regulation of protein degradation by O-GlcNAcylation: crosstalk with ubiquitination. Molecular & Cellular Proteomics. 12(12): 3489-97.
4. Ruan HB, Singh JP, Li MD, Wu J, Yang, X. (2013). Cracking the O-GlcNAc code in metabolism. Trends in Endocrinology & Metabolism. 24(6): 301-309.
5. Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S, Zhao L, Bennett AM, Samuel VT, Wu J, Yates JR, Yang X. (2012). O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metabolism. 16(2): 226-237.

Fig. 1: PTMs mediate hormonal & nutritional regulation of metabolism.

Fig. 2: The HBP pathway and O-GlcNAcylation. Modified from Hart et al, 2011.