Sulforaphane Reduces SAMHD1 Phosphorylation To Protect Macrophages from HIV-1 Infection.

ABSTRACT

The cellular protein SAMHD1 is important for DNA repair, suppressing LINE elements, controlling deoxynucleoside triphosphate (dNTP) concentrations, maintaining HIV-1 latency, and preventing excessive type I interferon responses. SAMHD1 is also a potent inhibitor of HIV-1 and other significant viral pathogens. Infection restriction is due in part to the deoxynucleoside triphosphatase (dNTPase) activity of SAMHD1 but is also mediated through a dNTPase-independent mechanism that has been described but not explored. The phosphorylation of SAMHD1 at threonine 592 (T592) controls many of its functions. Retroviral restriction, irrespective of dNTPase activity, is linked to unphosphorylated T592. Sulforaphane (SFN), an isothiocyanate, protects macrophages from HIV infection by mobilizing the transcription factor and antioxidant response regulator Nrf2. Here, we show that SFN and other clinically relevant Nrf2 mobilizers reduce SAMHD1 T592 phosphorylation to protect macrophages from HIV-1. We further show that SFN, through Nrf2, triggers the upregulation of the cell cycle control protein p21 in human monocyte-derived macrophages to contribute to SAMHD1 activation. We additionally present data that support another, potentially redox-dependent mechanism employed by SFN to contribute to SAMHD1 activation through reduced phosphorylation. This work establishes the use of exogenous Nrf2 mobilizers as a novel way to study virus restriction by SAMHD1 and highlights the Nrf2 pathway as a potential target for the therapeutic control of SAMHD1 cellular and antiviral functions. IMPORTANCE Here, we show, for the first time, that the treatment of macrophages with Nrf2 mobilizers, known activators of antioxidant responses, increases the fraction of SAMHD1 without a regulatory phosphate at position 592. We demonstrate that this decreases infection of macrophages by HIV-1. Phosphorylated SAMHD1 is important for DNA repair, the suppression of LINE elements, the maintenance of HIV-1 in a latent state, and the prevention of excessive type I interferon responses, while unphosphorylated SAMHD1 blocks HIV infection. SAMHD1 impacts many viruses and is involved in various cancers, so knowledge of how it works and how it is regulated has broad implications for the development of therapeutics. Redox-modulating therapeutics are already in clinical use or under investigation for the treatment of many conditions. Thus, understanding the impact of redox modifiers on controlling SAMHD1 phosphorylation is important for many areas of research in microbiology and beyond.