SAMHD1’s protein expression profile in humans

Abstract

The deoxynucleoside triphosphate triphosphohydrolase and 3' → 5' exonuclease SAMHD1 restricts HIV-1 infection in noncycling hematopoietic cells in vitro, and SAMHD1 mutations are associated with AGS. Little is known about the in vivo expression and functional regulation of this cellular factor. Here, we first assessed the SAMHD1 protein expression profile on a microarray of 25 human tissues from >210 donors and in purified primary cell populations. In vivo, SAMHD1 was expressed in the majority of nucleated cells of hematopoietic origin, including tissue-resident macrophages, DCs, pDCs, all developmental stages of thymic T cells, monocytes, NK cells, as well as at lower levels in B cells. Of note, SAMHD1 was abundantly expressed in HIV target cells residing in the anogenital mucosa, providing a basis for its evaluation as a cellular factor that may impact the efficiency of HIV transmission. Next, we examined the effect of the activation status and proinflammatory cytokine treatment of cells on expression and phosphorylation of SAMHD1. Activated, HIV-susceptible CD4(+) T cells carried pSAMHD1(T592), whereas resting CD4(+) T cells and macrophages expressed the unphosphorylated protein with HIV-restrictive activity. Surprisingly, stimulation of these primary cells with IFN-α, IFN-γ, IL-4, IL-6, IL-12, IL-18, IL-27, or TNF-α affected neither SAMHD1 expression levels nor threonine 592 phosphorylation. Only IL-1β moderately down-regulated SAMHD1 in activated CD4(+) T cells. Taken together, this study establishes the first cross-sectional protein expression profile of SAMHD1 in human tissues and provides insight into its cell cycle-dependent phosphorylation and unresponsiveness to multiple proinflammatory cytokines.

SAMHD1: At the Crossroads of Cell Proliferation, Immune Responses, and Virus Restriction

“…It is thus not surprising to find that mutations in SAMHD1, associated with low protein expression, have been identified with a relatively high prevalence (up to 11%) in patients with relapsed/refractory chronic lymphocytic leukemia (CLL) [69]. Although predominantly in hematopoietic cells, SAMHD1 appears to be widely expressed in nontransformed tissues throughout the human body [70]. Further research should evaluate the possible role of SAMHD1 in various types of malignancy.…”

Vpx overcomes a SAMHD1-independent block to HIV reverse transcription that is specific to resting CD4 T cells

“…Phosphorylation of SAMHD1 at threonine 592 (pSAMHD1-T592) correlates with a loss of its HIV-restrictive capacity (21,22). Reprobing the immunoblot with an affinitypurified, T592 phosphosite-specific polyclonal rabbit antiserum (23) provided no evidence for an induction of this inactivating phosphorylation by any of the Vpx alleles, whereas cycling THP-1 cells displayed strong antibody reactivity (Fig. 1E).…”

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

“…While the precise function of DCIP (SAMHD1) remained unknown, it was subsequently determined to be upregulated in lung fibroblasts in response to TNF-⍺ or LPS induced acute injury in an IRF-1 dependent manner (95). Further studies eventually elucidated the integral function the enzyme performs in nucleotide metabolism and innate immunity within the cell, and in keeping with this critical role, SAMHD1 was revealed to be widely expressed in most human cells (96). …”

“…Quiescent primary human fibroblasts demonstrated a dramatic increase in SAMHD1 protein levels over proliferating fibroblasts, and this increase in SAMHD1 coincided with a decrease in intracellular dNTP pools (97). In contrast to fibroblasts, SAMHD1 is constitutively expressed at high levels in both cycling and non-cycling myeloid and lymphoid cells, including monocytes, macrophages, dendritic cells, and CD4+ T-cells, although its activity can be differentially regulated by post-translational modification (96, 98, 99). There is also experimental evidence to suggest that terminal differentiation of monocytes into macrophages or dendritic cells can further increase the expression levels of SAMHD1 (100).…”

“…Not all cells however, including macrophages, dendritic cells, and CD4+ T-Cells, exhibit an increase in SAMHD1 protein expression following exposure to IFN1 (96, 102, 109, 111). This discrepancy may be in part explained by the already elevated levels of SAMHD1 or by the inability of specific cell types to respond to IFN1 exposure by downregulating microRNAs that post-transcriptionally repress SAMHD1 translation (112).…”