Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification

Corey H. Yu, Akash Bhattacharya, Mirjana Persaud, Alexander B. Taylor, Zhonghua Wang, Angel Bulnes-Ramos, Joella Xu, Anastasia Selyutina, Alicia Martinez-Lopez, Kristin Cano, Borries Demeler, Baek Kim, Stephen C. Hardies, Felipe Diaz-Griffero () and Dmitri N. Ivanov ()
Additional contact information
Corey H. Yu: UT Health San Antonio
Akash Bhattacharya: UT Health San Antonio
Mirjana Persaud: Albert Einstein College of Medicine
Alexander B. Taylor: UT Health San Antonio
Zhonghua Wang: UT Health San Antonio
Angel Bulnes-Ramos: Albert Einstein College of Medicine
Joella Xu: Emory School of Medicine
Anastasia Selyutina: Albert Einstein College of Medicine
Alicia Martinez-Lopez: Albert Einstein College of Medicine
Kristin Cano: UT Health San Antonio
Borries Demeler: University of Lethbridge
Baek Kim: Emory School of Medicine
Stephen C. Hardies: UT Health San Antonio
Felipe Diaz-Griffero: Albert Einstein College of Medicine
Dmitri N. Ivanov: UT Health San Antonio

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, and the enzymatic activity of the protein—dephosphorylation of deoxynucleotide triphosphates (dNTPs)—implicates enzymatic dNTP depletion in innate antiviral immunity. Here we show that the allosteric binding sites of the enzyme are plastic and can accommodate oligonucleotides in place of the allosteric activators, GTP and dNTP. SAMHD1 displays a preference for oligonucleotides containing phosphorothioate bonds in the Rp configuration located 3’ to G nucleotides (GpsN), the modification pattern that occurs in a mechanism of antiviral defense in prokaryotes. In the presence of GTP and dNTPs, binding of GpsN-containing oligonucleotides promotes formation of a distinct tetramer with mixed occupancy of the allosteric sites. Mutations that impair formation of the mixed-occupancy complex abolish the antiretroviral activity of SAMHD1, but not its ability to deplete dNTPs. The findings link nucleic acid binding to the antiretroviral activity of SAMHD1, shed light on the immunomodulatory effects of synthetic phosphorothioated oligonucleotides and raise questions about the role of nucleic acid phosphorothioation in human innate immunity.

Date: 2021
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DOI: 10.1038/s41467-021-21023-8

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