Patricia Berninsone, Ph.D.

Project 2: Secretion of Signaling Molecules

Roles of p24 Proteins in Trafficking of Intercellular Signaling Proteins and Glycosylation of Secreted Proteins

In eukaryotes, the secretory pathway sorts and delivers proteins to intracellular compartments, the plasma membrane, and the extracellular space. Many secretory proteins are modified by glycosylation in the endoplasmic reticulum (ER) and the Golgi apparatus. The resulting carbohydrate modifications are structurally diverse and contribute to most interactions at the cell surface.

Using the nematode Caenorhabditis elegans, we have identified three genes which, when mutated, unmask glycosylated epitopes on the cuticle surface and cause multiple defects including cell migration abnormalities. This project uses C.elegans to investigate the roles of p24 proteins in the modulation of protein glycosylation status and the interactions of p24 proteins with extracellular signaling pathways, using a combination of genetic, biochemical and proteomic approaches. Neuronal migration will facilitate the design of strategies to clarify underlying links between glycosylation defects and clinical presentation in the trafficking-associated congenital disorders of glycosylation (CDGs). The CDG are a group of recently discovered human genetic disorders that lead to abnormal glycan structures on glycoproteins and cause mental retardation, seizures, hypotonia, liver malfunction, coagulopathy and dysmorphia. About 25% of CDG patients die from severe infections or multiple organ failure.

A better understanding of protein glycosylation and secretion will help to better understand human disease mechanisms in congenital disorders of glycosylation and to develop new therapies for patients who suffer from mental retardation, seizures, hypotonia, liver malfunction, coagulopathy and dysmorphia.