| |
| author |
Lauren DiRienzo
| | title |
Investigating the Role of the Interaction of USP18 With Proteins of the IFI16/cGAS Pathway
| | abstract |
Interferon-inducible protein 16 (IFI16) and cyclic GMP-AMP synthase (cGAS) are DNA
sensor pattern recognition receptors (PRRs) that bind to viral double stranded DNA and activate
the STING protein to result in the production of type I interferon (IFN) and the innate immune
response. While activation of PRR signaling is very important for defending the body against
microbes, dysregulated or excessive innate immune activation can lead to pathological
inflammation and autoimmune disease (Liu and Cao, 2016). Therefore, regulation of this
signaling is vital to ensure that the innate immune response can successfully eliminate pathogens
while avoiding causing damage to the host. We investigated one possible interacting partner and
regulator of this pathway, a deubiquitinase called ubiquitin specific protease 18 (USP18). USP18
acts to remove ISG15 from its target substrates, which is hypothesized to destabilize them
(Basters et al., 2018). One important protein in the IFI16/cGAS-STING pathway, the
transcription factor interferon regulatory factor 3 (IRF3), has been shown to be ISGylated to
maintain its active state in other systems (Dzimianski et al., 2019; Cruz 2022, Liu et al., 2021).
By removing ISG15 from IRF3, USP18 may act as a specific negative regulator. Previous studies
have also shown that USP18 acts as a general negative regulator of the type I IFN pathway in
response to other stimuli, but specific interactions with DNA-sensing pathway proteins have not
been explored. In this study, we show that USP18 physically interacts with IFI16 through
co-immunoprecipitation experiments. Additionally, we determined that USP18 acts as a negative
regulator of the type I IFN response to DNA and RNA sensing by performing qPCR to show that
USP18-deficient THP-1 cells had increased levels of ISG56 transcripts, a measure of the type I
IFN response, compared to normal THP-1 cells. These findings indicate that USP18 may be
involved in the IFI16/cGAS-STING pathways in a way that contributes to its role in controlling
levels of type I IFN.
| | school |
The College of Liberal Arts, Drew University
| | degree |
B.S. (2023)
|
| advisor |
Dr. Stephen Dunaway
Dr. Brianne Barker
|
| full text | LDiRienzo.pdf - requires Drew uLogin |
| |
