Characterization of OST-based activation of apoptosis

Pepperdine University, Malibu CA

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Abstract

DESCRIPTION (provided by applicant) The proper synthesis and processing of proteins is critical to normal cellular function. The endoplasmic reticulum (ER) is an organelle found in all higher organisms, whose central role in cell function is to mediate protein synthesis. Humans afflicted with abnormal protein processing in the ER and a related organelle, the Golgi body, suffer from devastating developmental abnormalities and comprise a broad category of disease known as Congenital Disorders of Glycosylation (CDGs). The key aspect of protein processing in the ER and Golgi is the addition of sugars to newly synthesized proteins, called glycosylation. This proposal seeks to characterize fundamental aspects of protein glycosylation, specifically how abnormal glycosylation influences the generation of signals within a cell. These signals are generated as a result of abnormal protein synthesis, which results in ER stress. The activation of ER stress can result in cell suicide (apoptosis), adaptation to the stress, growth arrest, or stimulation of localized inflammation. Our long-term goals focus upon how cells activate apoptosis following ER stress. This proposed project will allow characterization of the molecules that carry this stress signal, and examine how this cell suicide is executed. The improper processing of proteins in the ER and Golgi causes mutations in a variety of genes, and the type of disease that results from such mutations depends upon the identity of the mutated protein. Cystic fibrosis patients suffer lung degeneration that is the result of ER stress-activated signals as a membrane protein is improperly glycosylated, and one type of inherited hypercholesterolemia (high cholesterol) is the result of ER-associated processing deficiencies of a signal receptor. The characterization of ER stress and its signaling mechanisms will offer vital insight into the cell biology of stressed cells, and will be valuable to our understanding of diseases that result from abnormal ER function/processing.