Studies on the Potential Regulation of USP30 by Omi/HtrA2 Protease

The intent of this thesis is to determine whether the deubiquitinating enzyme ubiquitin specific protease 30 (USP30) is cleaved by Omi/HtrA2 (hereafter referred to as Omi) protease during mitochondrial stress. USP30 is a mitochondrial protein that is anchored in the outer mitochondrial membrane and has components in the intermembrane space (IMS) as well as in the cytoplasm. USP30\u27s IMS component has a six-amino-acid sequence that is very similar to Omi\u27s consensus cleavage sites. Under normal conditions, Omi resides exclusively within the IMS; therefore, if Omi were to cleave USP30, it would target the part of the protein located in the IMS component. Omi is known to play a crucial role in a variety of diseases including cancers, neurodegenerative, and metabolic disorders. Since Omi is a serine protease, it is assumed to carry its normal function through the direct cleavage and degradation of specific substrates. If USP30 deubiquitinase is a bona fide substrate of Omi, this will provide new and important information on the mechanism by which Omi regulates the polyubiquitination process during mitochondrial stress