Cyclin D3-dependent control of the dNTP pool and HIV-1 replication in human macrophages.
Cyclins control the activation of cyclin-dependent kinases (CDK), which in turn, control the cell cycle and cell division. Intracellular availability of deoxynucleotides (dNTP) plays a fundamental role in cell cycle progression. SAM domain and HD domain-containing protein 1 (SAMHD1) degrades nucleotide triphosphates and controls the size of the dNTP pool. SAMHD1 activity appears to be controlled by CDK. Here, we show that knockdown of cyclin D3 a partner of CDK6 and E2 a partner of CDK2 had a major impact in SAMHD1 phosphorylation and inactivation and led to decreased dNTP levels and inhibition of HIV-1 at the reverse transcription step in primary human macrophages. The effect of cyclin D3 RNA interference was lost after degradation of SAMHD1 by HIV-2 Vpx, demonstrating the specificity of the mechanism. Cyclin D3 inhibition correlated with decreased activation of CDK2. Our results confirm the fundamental role of the CDK6-cyclin D3 pair in controlling CDK2-dependent SAMHD1 phosphorylation and dNTP pool in primary macrophages.
a AIDS Research Institute-IrsiCaixa and AIDS Unit; Hospital Germans Trias i Pujol; Universitat Autonoma de Barcelona ; Badalona , Spain.
Alba
A
Ruiz
Eduardo
E
Pauls
Roger
R
Badia
Javier
J
Torres-Torronteras
Eva
E
Riveira-Muñoz
Bonaventura
B
Clotet
Ramon
R
Martí
Ester
E
Ballana
José A
JA
Esté
D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000378:metabolism*; D003854:Deoxyribonucleotides / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008264:Macrophages / Q000502:physiology* / Q000821:virology; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D010766:Phosphorylation; D034622:RNA Interference; D000076106:SAM Domain and HD Domain-Containing Protein 1; D014779:Virus Replication / Q000502:physiology*
C534696:CCND3 protein, human; D056743:Cyclin D3; D003854:Deoxyribonucleotides; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D000076106:SAM Domain and HD Domain-Containing Protein 1; C484280:SAMHD1 protein, human; D020559:Monomeric GTP-Binding Proteins
HIV-1; SAMHD1; cyclin; cyclin-dependent kinase; virus restriction