SAMHD1 controls cell cycle status, apoptosis and HIV-1 infection in monocytic THP-1 cells

Abstract

SAMHD1 limits HIV-1 infection in non-dividing myeloid cells by decreasing intracellular dNTP pools. HIV-1 restriction by SAMHD1 in these cells likely prevents activation of antiviral immune responses and modulates viral pathogenesis, thus highlighting a critical role of SAMHD1 in HIV-1 physiopathology. Here, we explored the function of SAMHD1 in regulating cell proliferation, cell cycle progression and apoptosis in monocytic THP-1 cells. Using the CRISPR/Cas9 technology, we generated THP-1 cells with stable SAMHD1 knockout. We found that silencing of SAMHD1 in cycling cells stimulates cell proliferation, redistributes cell cycle population in the G1/G0 phase and reduces apoptosis. These alterations correlated with increased dNTP levels and more efficient HIV-1 infection in dividing SAMHD1 knockout cells relative to control. Our results suggest that SAMHD1, through its dNTPase activity, affects cell proliferation, cell cycle distribution and apoptosis, and emphasize a key role of SAMHD1 in the interplay between cell cycle regulation and HIV-1 infection.

Inhibition of Vpx-Mediated SAMHD1 and Vpr-Mediated Host Helicase Transcription Factor Degradation by Selective Disruption of Viral CRL4 (DCAF1) E3 Ubiquitin Ligase Assembly

“…The Vpx-CRL4A (DCAF1) E3 ubiquitin ligase complex (8,48) can degrade the restriction factor SAM domain and HD domain-containing protein 1 (SAMHD1) (49,50), which inhibits HIV-1 infection of myeloid-lineage cells as well as resting CD4 ϩ T cells by depleting cellular deoxynucleoside triphosphates (dNTPs) to a level at which the viral reverse transcriptase cannot function (4,(51)(52)(53)(54)(55)(56). To efficiently block Vpx function, one promising approach is to directly impair the interaction between Vpx and CRL4 (DCAF1) E3 ligase.…”

SAMHD1: Recurring roles in cell cycle, viral restriction, cancer, and innate immunity

“…SAMHD1 is widely established as a central regulator of dNTP pool dynamics within cells and as such its catalytic activity can directly influence the replicative capacity of the cell (97, 133–136). Silencing or degradation of SAMHD1 results in elevated dNTP pools and altered growth kinetics as evidenced by studies that demonstrate an increased retention of cells in the G 1 phase with a corresponding loss in S-phase cells (97, 133, 137).…”

“…Silencing or degradation of SAMHD1 results in elevated dNTP pools and altered growth kinetics as evidenced by studies that demonstrate an increased retention of cells in the G 1 phase with a corresponding loss in S-phase cells (97, 133, 137). Intriguingly, the precise effect of knocking down SAMHD1 on proliferative capacity appears to depend on the specific cell type.…”

“…Intriguingly, the precise effect of knocking down SAMHD1 on proliferative capacity appears to depend on the specific cell type. Fibroblasts and THP-1 cells have been reported to grow either slower or faster, respectively, in the absence of SAMHD1 (97, 133). In THP-1 cells, the increased dNTP pools and enhanced proliferative capacity were accompanied by a reduction in spontaneous apoptosis (133).…”

“…Fibroblasts and THP-1 cells have been reported to grow either slower or faster, respectively, in the absence of SAMHD1 (97, 133). In THP-1 cells, the increased dNTP pools and enhanced proliferative capacity were accompanied by a reduction in spontaneous apoptosis (133). Conversely, up-regulation of SAMHD1 can also alter growth kinetics by contributing to a quiescent or differentiated phenotype in fibroblasts and THP-1 cells by coordinating with other nucleotide metabolizing enzymes to maintain reduced dNTP levels (97, 138).…”