Thesis

Understanding the Regulation of Proteasome Homeostasis upon Stress

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Dysregulation of the ubiquitin-proteasome system (UPS) leads to the accumulation of aggregationprone proteins which has been linked to neurodegeneration and cancer. The 26S proteasome is acentral component of the UPS. It assembles by the successive recruitment of the 33 different
proteasome subunits which is assisted by proteasome assembly chaperones: five for the CP and five
for the RP. RPACs are translationally induced upon stress to assemble more functional proteasomes.
Most recently, it has been shown that the deletion of the 5’ untranslated region (UTR) of one RPAC
mRNA, Adc17, completely abolished its translation. This study aims to investigate the impact of UTR
deletion on RPACs translation and to monitor mRNA localisation relative to the actin cytoskeleton.
Using the CRISPR/Cas9 system, we revealed that 5’UTR is responsible for both increased mRNA
translation upon stress and mRNA stability in Nas6, while 3’UTR mainly regulate mRNA stability.
Furthermore, confocal microscopy analysis showed that NAS6 mRNA is interacting with the actin
cytoskeleton, as previously reported for ADC17. Previous data showed that ADC17 mRNA is recruited
to cortical actin patches for translation upon stress, in an Ede1-dependent manner. Therefore, the
second part of this study seeks to know if Ede1 phase separation is important for this process.
CRISPR/Cas9 deletion of the phase-separating region of Ede1 phenocopied ede1 cells, confirming that
phase separation is important for Ede1 function in regulating proteasome assembly. Together, these
results improve our current understanding of proteasome biology, a key step in developing new
strategy to restore proteasome function in diseases.

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Availability

Detail Information

Series Title

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Call Number

BM 23-012

Publisher

i3L, Jakarta : i3L, Jakarta., 2023

Collation

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Language

English

ISBN/ISSN

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Classification

NONE

Content Type

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Media Type

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Carrier Type

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Edition

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Subject(s)

Proteasome
Proteasome Assembly Chaperone
Stress response
RNA regulation
CRISPRCas9

Specific Detail Info

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Statement of Responsibility

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