Our laboratory is part of the emerging field of glycobiology, which focuses on the molecular interactions of sugars distinct from their nutritional role. We work with glucose and its lesser-known structural cousins, such as mannose, as components of sugar polymers known as glycans. Glycans can covalently attach to proteins to form glycoproteins or to lipids to form glycolipids. Glycans are recognized by highly specific glycan-binding proteins called lectins.

Glycans play roles in protein sorting and folding, cell-cell interaction, signaling, pathogen binding, and many other functions. There are approximately 100 human genetic diseases caused by mistakes in synthesizing or processing glycans. Our lab uses a combination of biochemistry, genetics, and cell biology to understanding how glycans work, and what goes wrong in diseases of glycan deficiency.

Our specific research interests are always evolving, but the research problems we are currently pursuing include:

Anti-viral signaling by free mannose-6-phosphate (M6P) and free glycans

We discovered that M6P is elevated in the cytosol of mammalian cells in response to infection by herpes simplex virus-1. Subsequently, we found that the elevated M6P concentrations dysregulate the pathway for protein glycosylation in the endoplasmic reticulum (ER) and cause the ER to become flooded with free glycans. Because assembly of viruses like herpes simplex-1 require ER glycosylation, we have proposed that M6P carries a host-defense signal that suppresses viral replication, and that the free glycans are anti-viral.

The roles of glycans in DNA-sensing pathways of innate and autoimmunity

TREX1 is a regulator of innate immunity, and patients with TREX1 defects have autoimmune disease. In collaboration with Nan Yan, Ph.D., we are exploring the hypothesis that TREX1 defects result in ER glycosylation abnormalities that result in clinical pathology.

Control of sugar metabolism by unfolded protein response (UPR) signaling

Dysfunction in the ER activates a family of signaling pathways known collectively as the UPR. We found that activation of the kinase domain of a key signaling protein termed IRE1 dramatically alters cellular sugar metabolism. Our goal is to identify novel protein substrates of the IRE1 kinase, which we speculate will regulate sugar metabolism and consequently alter cellular glycans.

Molecular basis for glycosylation defects in PMM2-CDG, a congenital disorder of glycosylation

The most common hereditary glycosylation disorder, PMM2-CDG, is due to loss of phosphomannomutase encoded by the gene PMM2. In collaboration with Richard Steet, Ph.D., and Heather Steet, Ph.D. at the University of Georgia Complex Carbohydrate Research Center, we are using zebrafish to model PMM2-CDG disease, and then employ biochemical methods to pinpoint the metabolic consequences of phosphomannomutase deficiency as well as test potential drug therapies.