SAMHD1 Phosphorylation Coordinates the Anti-HIV-1 Response by Diverse Interferons and Tyrosine Kinase Inhibition

MBio
Matthew A SzaniawskiVicente Planelles

Abstract

Macrophages are susceptible to human immunodeficiency virus type 1 (HIV-1) infection despite abundant expression of antiviral proteins. Perhaps the most important antiviral protein is the restriction factor sterile alpha motif domain and histidine/aspartic acid domain-containing protein 1 (SAMHD1). We investigated the role of SAMHD1 and its phospho-dependent regulation in the context of HIV-1 infection in primary human monocyte-derived macrophages and the ability of various interferons (IFNs) and pharmacologic agents to modulate SAMHD1. Here we show that stimulation by type I, type II, and to a lesser degree, type III interferons share activation of SAMHD1 via dephosphorylation at threonine-592 as a consequence of signaling. Cyclin-dependent kinase 1 (CDK1), a known effector kinase for SAMHD1, was downregulated at the protein level by all IFN types tested. Pharmacologic inhibition or small interfering RNA (siRNA)-mediated knockdown of CDK1 phenocopied the effects of IFN on SAMHD1. A panel of FDA-approved tyrosine kinase inhibitors potently induced activation of SAMHD1 and subsequent HIV-1 inhibition. The viral restriction imposed via IFNs or dasatinib could be overcome through depletion of SAMHD1, indicating that their effects ...Continue Reading

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Citations

Oct 10, 2018·The Journal of Infectious Diseases·Matthew A SzaniawskiVicente Planelles
Aug 14, 2020·PLoS Pathogens·Rachel S ResopAlberto Bosque
Sep 12, 2019·Current HIV/AIDS Reports·Sara Rodríguez-MoraMayte Coiras
May 2, 2020·Current HIV/AIDS Reports·Matthew A Szaniawski, Adam M Spivak
Dec 24, 2018·Frontiers in Immunology·Marta Colomer-LluchJulia G Prado
Oct 23, 2020·International Journal of Molecular Sciences·Tinus SchynkelWim Trypsteen

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Methods Mentioned

BETA
flow cytometry
RNA-seq
enzyme-linked immunosorbent assay
transfection
ELISA
PCR
Assay

Software Mentioned

GraphPad Prism
GraphPad

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