CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain

SAMHD1 is a nuclear deoxyribonucleoside triphosphate triphosphohydrolase that contributes to the control of cellular deoxyribonucleoside triphosphate (dNTP) pool sizes through dNTP hydrolysis and modulates the innate immune response to viruses. CyclinA2-CDK1/2 phosphorylates SAMHD1 at Thr-592, but how this modification controls SAMHD1 functions in proliferating cells is not known. Here, we show that SAMHD1 levels remain relatively unchanged during the cell division cycle in primary human T lymphocytes and in monocytic cell lines. Inactivation of the bipartite cyclinA2-CDK-binding site in the SAMHD1 C terminus described herein abolished SAMHD1 phosphorylation on Thr-592 during S and G₂ phases thus interfering with DNA replication and progression of cells through S phase. The effects exerted by Thr-592 phosphorylation-defective SAMHD1 mutants were associated with activation of DNA damage checkpoint and depletion of dNTP concentrations to levels lower than those seen upon expression of wild type SAMHD1 protein. These disruptive effects were relieved by either mutation of the catalytic residues of the SAMHD1 phosphohydrolase domain or by a Thr-592 phosphomimetic mutation, thus linking the Thr-592 phosphorylation state to the control of SAMHD1 dNTPase activity. Our findings support a model in which phosphorylation of Thr-592 by cyclinA2-CDK down-modulates, but does not inactivate, SAMHD1 dNTPase in S phase, thereby fine-tuning SAMHD1 control of dNTP levels during DNA replication.     

Type I interferon in neurological disease—The devil from within

The members of the type I interferon (IFN-I) family of cytokines are pleiotropic factors that have seminal roles in host defence, acting as antimicrobial and antitumor mediators as well as potent immunomodulatory factors that bridge the innate and adaptive immune responses. Despite these beneficial actions there is mounting evidence that link inappropriate or chronic production of IFN-I in the CNS to the development of a number of severe neuroinflammatory disorders. The most persuasive example is the genetically determined inflammatory encephalopathy, Aicardi–Goutières syndrome (AGS) in which patients have chronically elevated IFN-α production in the CNS. The presentation of AGS can often mimic congenital viral infection, however, molecular genetic studies have identified mutations in six genes that can cause AGS, most likely via dysregulated nucleic acid metabolism and activation of the innate immune response leading to increased intrathecal production of IFN-α. The role of IFN-α as a pathogenic factor in AGS and other neurological disorders has gained considerable support from experimental studies. In particular, a transgenic mouse model with CNS-restricted production of IFN-α replicates many of the cardinal neuropathologic features of AGS and reveal IFN-I to be the “devil from within”, mediating molecular and cellular damage within the CNS. Thus, targeting IFN-I may be an effective strategy for the treatment of AGS as well as some other autoimmune and infectious neurological “interferonopathies”.