Student Theses and Dissertations

Author

Irit Shachrai

Date of Award

2017

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Steller Laboratory

Abstract

The regulation of the ubiquitin-proteasome system (UPS) has been the subject of a vast body of work because of its implication in normal development and a wide range of diseases. The UPS controls the degradation of a large number of cellular proteins and thereby regulates essential cellular processes critical for cellular adaptation and more. Amongst the main processes are removal of mis-folded and potentially toxic proteins, cell’s loss of protein quality control is often associated with muscle atrophy and neurodegenerative diseases. The proteasome is subject to tight regulation, as many different proteins govern its transcription, assembly, stability and activity. Consequently, its regulation is extremely complex and even further complicated by the fact that all the above events are responsive to changing cellular environment and different pathophysiological conditions. Although the proteasome has been studied extensively, much still remains unknown, especially missing is a detailed mechanism as to how its complexed and multi-phased assembly adapts to proteotoxic stress. In this thesis I used a proteasome impaired genetic background to screen for suppressors of proteotoxic stress which modify proteasomes adaptive tress response. To my surprise I identified a core 20S subunit of the proteasome, α1 subunit. This finding uncovered its functional interaction with a yet uncharacterized regulator of proteasome stability in Drosophila, Ecm29 (CG8858). Whereas much is known of proteasome stress response at the level of its expression, very little is known of adaptive responses through alternative assembly. The results of this thesis suggest a new mechanism for proteasome stress adaption through modified assembly. To date most studies of proteasome regulation focused on the regulatory particle as master regulator and overlooked participation of the proteasome core particle in regulatory function. This thesis exemplifies the significance of the core particle, specifically its α ring, as an integral entity in the regulation of protein degradation by the proteasome. The overall findings demonstrate vitality of the proteasomes as active players in the response to proteotoxic stress. Furthermore, they define regulation of proteasome assembly as a mechanism to control suitable protein turnover and healthy cellular function.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Available for download on Wednesday, May 02, 2018

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