Understanding the Mechanism by which Sulforaphane Promotes SAMHD1 Activation to Protect Macrophages Against HIV Infection
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Issue Date
2022-08
Authors
Fazzari, Vincent A. '22
Degree
MS in Molecular Biosciences
Advisor
Singh, Vir
Committee Members
Sharifi, H. John
Malik, Meenakshi
Shi, Binshan
Malik, Meenakshi
Shi, Binshan
Journal Title
Journal ISSN
Volume Title
Abstract
The human immunodeficiency virus (HIV) is the causative agent of acquired immunodeficiency syndrome (AIDS). To date, HIV/AIDS has killed an estimated 40 million people. There is no cure, no vaccine, and current therapies are burdened with high cost and toxicity. Therefore, further study of HIV is necessary. Sulforaphane (SFN), a compound found in cruciferous vegetables, was shown to block HIV infection of macrophages through activation of the transcription factor Nrf2. Follow up, unpublished, work by H. John Sharifi, PhD and Dakota Paine, M.S. found that SFN promotes the absence of an inhibitory phosphate from the antiviral protein SAMHD1. The exact mechanism of unphosphorylated SAMHD1 by SFN is unclear. The goal of this work was to uncover potential ways that SFN can yield unphosphorylated SAMHD1. Our central hypothesis is that SFN, acting through Nrf2, upregulates p21 and drives SAMHD1 into the nucleus to promote SAMHD1 dephosphorylation and protection against HIV. This hypothesis is based on an observation by Dr. Sharifi and Mr. Paine that SFN upregulates p21, also known as cyclin-dependent kinase inhibitor 1, in primary macrophages. p21 is a cell cycle control protein that has been previously shown to inhibit SAMHD1 phosphorylation. This hypothesis is additionally based on work showing that SAMHD1 accumulates in the cytosol under oxidizing conditions and that SFN promotes reducing conditions. This hypothesis was tested to determine the influence on SAMHD1 phosphorylation. Here, we first confirmed that SAMHD1 is required for the antiviral effect of SFN. We then established that p21 levels do not necessarily connect SFN to unphosphorylated SAMHD1. We further show that SFN does not change the intracellular location of SAMHD1.
Citation
Fazzari V. Understanding the mechanism by which sulforaphane promotes SAMHD1 activation to protect macrophages against HIV infection [thesis]. Ann Arbor (MI): Proquest LLC; 2022. 65 p.
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