Access Type

Open Access Dissertation

Date of Award

January 2020

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Pharmacology

First Advisor

Sokol V. Todi

Abstract

Ubiquitin is an 8.5 kDa post-translational modifier involved in essentially all eukaryotic cellular processes. Through a process called ubiquitination, ubiquitinating enzymes chemically attach ubiquitin to substrate proteins to control their fates, resulting in anything from their recruitment into signaling pathways to their proteasomal degradation, with a plethora of possibilities in between. Ubiquitin molecules can also be attached to one another, resulting in poly-ubiquitin chains with various effects depending on the number of ubiquitin molecules and the specific amino acid residues used to link them together. While most poly-ubiquitin in the cell exists as conjugated species, there are also untethered poly-ubiquitin species that are not attached to substrates. These unanchored ubiquitin chains have been previously classified as toxic byproducts that interfere with proteasomal function in vitro and in yeast, and are thus believed to be disassembled rapidly to avoid toxicity. Conversely, several studies have indicated a signaling role for certain types of unanchored ubiquitin chains in innate immunity and stress responses. Recent work from our lab that places untethered poly-ubiquitin in an in vivo setting, the fruit fly Drosophila melanogaster, has established a more nuanced existence for these chains. By manipulating the chemical properties of one type of untethered ubiquitin chain – linear poly-ubiquitin – we have shown that these chains are not always toxic in vivo. Under normal circumstances, they are innocuous, readily degraded by the proteasome, and used by endogenous ubiquitination machinery that transfers them to substrates in toto. It is only under certain conditions that they become noxious and elicit a cellular response; for example, when unanchored, linear ubiquitin chains cannot be ubiquitinated, they induce aberrant NF-κB signaling, resulting in premature death in flies. Our work invites a re-evaluation of the credence that untethered poly-ubiquitin is always toxic, and more broadly points to untapped potential for unanchored chain involvement in additional pathways in vivo.

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