TY - JOUR
T1 - Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification
AU - Yu, Corey H.
AU - Bhattacharya, Akash
AU - Persaud, Mirjana
AU - Taylor, Alexander B.
AU - Wang, Zhonghua
AU - Bulnes-Ramos, Angel
AU - Xu, Joella
AU - Selyutina, Anastasia
AU - Martinez-Lopez, Alicia
AU - Cano, Kristin
AU - Demeler, Borries
AU - Kim, Baek
AU - Hardies, Stephen C.
AU - Diaz-Griffero, Felipe
AU - Ivanov, Dmitri N.
N1 - Funding Information:
This work was supported in part by NIH AI104476 and AI136697 (D.N.I.), NIH AI150455 (F.D.-G.), NIH AI136581 and AI150451 (B.K.), and NIH GM120600 (B.D.). The Institutional Core Facilities at the UT Health Science Center at San Antonio are supported in part as Shared Resources (X-ray crystallography, NMR, analytical ultracentrifugation, and mass spectrometry) of the Mays Cancer Center—UT Health San Antonio (NIH P30 CA054174) and by the Office of the Vice President for Research. Supercomputer allocations were provided by NSF MCB070038-A13 (B.D.) and UT TG457201 (B.D.). This work is based on research conducted at the Northeastern Collaborative Access Team beamlines, which are funded by the National Institute of General Medical Sciences from the National Institute of Health (P30 GM124165). The Eiger 16M detector on 24-1D-E is funded by a NIH-ORIP HEI grant (S10OD021527). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-021-21023-8
DO - 10.1038/s41467-021-21023-8
M3 - Article
C2 - 33531504
AN - SCOPUS:85100335561
SN - 2041-1723
VL - 12
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 731
ER -