The Role of Chikungunya nsP3 in Regulating G3BP Activity, Stress Granule Formation and Drug Efficacy

Loading...
Thumbnail Image
File version
Author(s)
Primary Supervisor

Kennedy, Hendrick

Other Supervisors

Watters, Dianne

Editor(s)
Date
2018-06
Size
File type(s)
Location
License
Abstract

Ras-GTPase activating protein SH3 domain binding proteins (G3BP) are a small family of RNA-binding proteins that have been implicated in regulating gene expression when a cell undergoes transformation or in response to external stimuli. Changes in the cellular expression of G3BPs are correlated to several cancers including head and neck, thyroid, colon, pancreatic and breast cancer. G3BPs are components of stress granules (SGs) and can regulate their formation. SGs are specialised ribonucleoprotein (RNP) particles that respond to cellular stresses, including chemotherapy, to triage mRNA with selected transcripts being degraded, stored or translated. The net result to the cell is a change in the gene expression which confers a survival response to the cell. This can include the upregulation of genes needed to survive external stresses and this can include the development of drug resistance in cells. Many viruses, including Chikungunya, target SG and dismantle the granules so that the cell cannot respond to the viral infection. Non-structural protein3 (nsP3), from the Chikungunya virus, has been shown to translocate G3BP from SG, and the inability of the cell to form SG is required for the virus to complete an infectious cycle. Interestingly, the formation of SG is correlated to drug-resistance and blocking their formation has been shown to reestablish the efficacy of the chemotherapeutic, bortezomib. The present study explored the disruption of SG formation, caused by the interaction of nsP3 with G3BP, and as a result restored cytotoxicity of bortezomib and improved the selectivity of the bortezomib for cancer cell lines when compared to HEK cells. In addition, the interaction of nsP3 with G3BP also disrupted the activity of G3BP and led to the significantly downregulation of G3BP target genes NDUFV1 and IFITM3. These findings represent a tool for future study into strategies to block G3BP activities and disrupt SG formation in anti-cancer therapeutics.

Journal Title
Conference Title
Book Title
Edition
Volume
Issue
Thesis Type

Thesis (Masters)

Degree Program

Master of Science (MSc)

School

School of Environment and Sc

Publisher link
Patent number
Funder(s)
Grant identifier(s)
Rights Statement
Rights Statement

The author owns the copyright in this thesis, unless stated otherwise.

Item Access Status
Note
Access the data
Related item(s)
Subject

Chikungunya

nsP3

G3BP activity

Stress

Granule formation

Drug efficacy

Persistent link to this record
Citation