Mouse SAMHD1 Has Antiretroviral Activity and Suppresses a Spontaneous Cell-Intrinsic Antiviral Response

Abstract

SUMMARY Aicardi-Goutières syndrome (AGS), a hereditary autoimmune disease, clinically and biochemically overlaps with systemic lupus erythematosus (SLE) and, like SLE, is characterized by spontaneous type I interferon (IFN) production. The finding that defects of intracellular nucleases cause AGS led to the concept that intracellular accumulation of nucleic acids triggers inappropriate production of type I IFN and autoimmunity. AGS can also be caused by defects of SAMHD1, a 3′ exonuclease and deoxy-nucleotide (dNTP) triphosphohydrolase. Human SAMHD1 is an HIV-1 restriction factor that hydrolyzes dNTPs and decreases their concentration below the levels required for retroviral reverse transcription. We show in gene-targeted mice that also mouse SAMHD1 reduces cellular dNTP concentrations and restricts retroviral replication in lymphocytes, macrophages, and dendritic cells. Importantly, the absence of SAMHD1 triggered IFN-β-dependent transcriptional upregulation of type I IFN-inducible genes in various cell types indicative of spontaneous IFN production. SAMHD1-deficient mice may be instrumental for elucidating the mechanisms that trigger pathogenic type I IFN responses in AGS and SLE.

Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

“…We base our conclusion on the following observations: (i) These cancers have mutations in SAMHD1, an enzyme responsible for the degradation of dNTPs; (ii) the identified SAMHD1 mutations negatively affect its dNTPase activity in vitro; and (iii) actively dividing hemizygous SAMHD1 +/− mouse embryos have increased dNTP pools compared with congenic WT embryos of the same age. Previous dNTP pool measurements were performed in various types of WT and SAMHD1 −/− homozygous cells, including E14.5 mouse embryonic fibroblasts (56,57), but, to our knowledge, ours is the first study to measure dNTP pools in hemizygous SAMHD1 mouse embryos. This observation is important because it demonstrates that cancer cells do not need to inactivate both SAMHD1 alleles to increase the dNTP pools.…”

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

“…In particular, there was no evidence of intracranial calcification, leukodystrophy, chilblain vasculitis or cardiomyopathy, clinical features associated with AGS in humans (Crow et al , 2015). Notably, histopathological signs of inflammation are also not evident in Samhd1 −/− mice, although activation of innate immune signalling does occur, with ISG upregulation evident (Behrendt et al , 2013; Rehwinkel et al , 2013). We therefore investigated whether this was also the case in Rnaseh2b A174T/A174T mice.…”

“…It will therefore be important to confirm that the innate immune pathways implicated in Trex1, Adar1 and now RNase H2 deficiency, through the use of mouse models, are also relevant to the human autoinflammatory phenotype in AGS patients in whom these genes are affected. Samhd1 −/− mice, like Rnaseh2b A174T/A174T mice, display an ISG response in the absence of detectable pathology (Behrendt et al , 2013; Rehwinkel et al , 2013). In contrast a strong ISG response in Adar1 null or editing‐deficient mice is associated with embryonic lethality (Mannion et al , 2014; Liddicoat et al , 2015; Pestal et al , 2015), and with autoinflammatory cardiomyopathy and multi‐tissue involvement in Trex1 −/− mice (Morita et al , 2004; Stetson et al , 2008; Gall et al , 2012).…”

CyclinA2-Cyclin-dependent Kinase Regulates SAMHD1 Protein Phosphohydrolase Domain

“…Loss-of-function SAMHD1 mutations in humans are associated with Aicardi-Goutières syndrome (AGS), 2 an auto-inflammatory genetically inherited interferonopathy, whose clinical presentation resembles congenital viral infection (3). In mice, SAMHD1 gene knock-out triggers spontaneous production of type I interferon (IFN) and up-regulation of type I IFN-stimulated genes (4,5). SAMHD1 also plays important roles in innate immunity to viral infections.…”

“…Loss of SAMHD1 function in individuals with AGS and transgenic models results in an increase in cellular dNTP concentrations (4,5,13). This, in turn, is thought to lead to inappropriate synthesis and/or presentation of cellular DNA to cytoplasmic sensors, thereby triggering production of type I IFN.…”