Date of Award
6-2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Program
Biomedical Sciences
Track
Neuroscience
Research Advisor
J. Paul Taylor, MD, PhD
Committee
William E. Armstrong, PhD; Mondira Kundu, MD, PhD; Peter J. McKinnon, PhD; Tanja Mittag, PhD
Keywords
G3BP, Nucleocapsid Protein, SARS-CoV-2, Stress Granule, Viral Genomic RNA
Abstract
G3BP1/2 are RNA-binding proteins that promote condensation to form stress granules in response to various cellular stresses, including viral infection. G3BP1/2 are prominent interactors of the nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the functional consequences of the G3BP-N interaction in the context of viral infection have remained unclear. Here we used structural and biochemical analyses to define the residues required for G3BP1-N interaction, followed by structure-guided mutagenesis of G3BP1 and N to selectively disrupt their interaction. We found that mutation of N-F17 led to selective loss of interaction with G3BP1 and consequent failure of the N protein to disrupt stress granule assembly. Introduction of SARS-CoV-2 bearing an F17A mutation in an in vivo hamster model resulted in significant decreases in viral replication, symptom severity, and pathology, suggesting that the G3BP1-N interaction promotes viral replication by suppressing the ability of G3BP1 to form stress granules.
ORCID
https://orcid.org/0009-0001-0590-2180
DOI
10.21007/etd.cghs.2023.0633
Recommended Citation
Yang, Zemin (https://orcid.org/0009-0001-0590-2180), "The Interaction Between Host G3BP and Viral Nucleocapsid Protein Regulates SARS-CoV-2 Replication" (2023). Theses and Dissertations (ETD). Paper 646. http://dx.doi.org/10.21007/etd.cghs.2023.0633.
https://dc.uthsc.edu/dissertations/646
Declaration of Authorship
Included in
Medical Cell Biology Commons, Medical Neurobiology Commons, Neurosciences Commons, Virus Diseases Commons