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Date of Award
Bachelor of Science (BS)
Department of Biology
Kimberly H. Slekar
The unfolded protein response (UPR) is a signal transduction cascade that mitigates low levels of misfolded protein stress in the endoplasmic reticulum (ER) in an effort to save the affected cell, while prolonged and/or acute ER stress leads to UPR-initiated apoptosis (programmed cell death). One putative step driving apoptosis is the cleavage of chaperones, proteins tasked to help misfolded proteins refold, by caspases, proteases essential to the execution of apoptosis. We are studying the nascent polypeptide-associated complex (NAC), a heterodimeric chaperone complex essential for viability, to determine if its beta subunit is cleaved by caspases during apoptosis to prevent the NAC from refolding proteins in a cell fated to die. To this end I am developing a western analysis protocol to assess the state of the βNAC homolog inhibitor of cell death-1 (ICD-1) in C. elegans experiencing misfolded protein stress. Initial results have identified an antibody with high affinity for a protein of similar molecular weight as ICD-1 that is depleted in animals treated with ICD-1 RNA interference (RNAi). Protein lysates isolated from animals experiencing chemically induced ER-specific misfolded protein stress have displayed altered western profiles consistent with cleavage of ICD-1. Further studies, including immunoprecipitations and protein sequencing, will provide independent confirmation of the specificity of our ICD-1 western analyses, while experiments in stressed C. elegans mutants defective for apoptosis will determine the causal relationship of apoptosis and cleavage of ICD- 1. If ICD-1 is cleaved by caspases during UPR-induced apoptosis, it will be the first evidence of the targeting of chaperones during the initiation and/or propagation of apoptosis, identifying a novel strategy that helps ensure cell death by eliminating proteins tasked with saving the cell.
Cicalese, Kyle, "The state of the translational chaperone ICD-1 during apoptosis in Caenorhabditis elegans" (2018). Senior Honors Projects, 2010-current. 527.