Abstract:
Proteins can occasionally behave aberrantly within the cell and cause a variety of physiological issues. Multiple pathways exist that resolve this problem and allow the cell to continue normal protein production. Endoplasmic Reticulum (ER)-Associated Degradation (ERAD) and Inner Nuclear Membrane-Associated Degradation (INMAD) are pathways that remove these misfolded and otherwise aberrant proteins. Dysfunction in either system may result in numerous pathologies, including those relating to cholesterol homeostasis and neurodegeneration. When misfolded proteins accumulate in the endoplasmic reticulum (ER stress), some of these misfolded proteins are unable to be removed. We hypothesize that there are proteins that work in both pathways (ER stress recovery and ERAD/INMAD), and when present in excess, can restore degradation. Using the model organism Saccharomyces cerevisiae, proteins involved these pathways will be studied. First, a plasmid harboring the gene for a known ERAD substrate that engages the translocon was created. Second, four unique yeast strains were created, each harboring a combination of gene knockouts that encode enzymes involved in both ERAD and INMAD degradation pathways. Understanding these protein quality mechanisms may facilitate the development of improved therapeutics for human disease.
