{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSterile α motif and histidine–aspartate domain‐containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTP) hydrolase that plays a vital role in cellular nucleotide homeostasis. By depleting the intracellular dNTP pool, SAMHD1 restricts retroviral replication—including that of HIV‐1—by limiting the substrates needed for reverse transcription. In addition, it is a key target of viral accessory proteins (e.g., Vpx), which counteract its restrictive function, and mutations in SAMHD1 have been implicated in autoimmune disorders such as Aicardi–Goutières syndrome as well as in certain cancers, highlighting its significance for genome maintenance and cellular defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct restriction of viral replication, SAMHD1 modulates innate immune pathways. It down‐regulates nuclear factor‐κB activation and type I interferon (IFN) induction in response to viral infections and inflammatory stimuli, thereby curbing potentially harmful overactivation of the immune response. Its enzymatic activity is finely tuned by allosteric effectors and by phosphorylation at key residues—such as threonine 592 in human and the homologous threonine 634 in mouse—with these modifications influencing its antiviral efficacy while only modestly affecting its dNTP hydrolase activity. This regulation is critical not only for antiviral defense but also for maintaining replication fidelity and controlling mutation rates during processes such as immunoglobulin gene hypermutation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vivo mouse models further underscore the multifaceted role of SAMHD1 in antiviral immunity and immune regulation. SAMHD1 deficiency leads to elevated cellular dNTP levels, spontaneous IFN production, and a dysregulated immune profile that can enhance viral replication and promote inflammatory pathology. Moreover, altered SAMHD1 function has been linked to impaired adaptive immune responses and has potential therapeutic implications, as precision medicine approaches targeting nucleotide imbalances (e.g., in leukemia) are under investigation. Collectively, SAMHD1 is a critical regulator of nucleotide metabolism and immune signaling, orchestrating responses that maintain genomic stability while balancing antiviral defense and inflammatory control."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "17"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Rebecca D Powell, Paul J Holland, Thomas Hollis, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Aicardi-Goutieres syndrome gene and HIV-1 restriction factor SAMHD1 is a dGTP-regulated deoxynucleotide triphosphohydrolase."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.C111.317628"}], "href": "https://doi.org/10.1074/jbc.C111.317628"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22069334"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22069334"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Rayk Behrendt, Tina Schumann, Alexander Gerbaulet, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mouse SAMHD1 has antiretroviral activity and suppresses a spontaneous cell-intrinsic antiviral response."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2013.07.037"}], "href": "https://doi.org/10.1016/j.celrep.2013.07.037"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23972988"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23972988"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jan Rehwinkel, Jonathan Maelfait, Anne Bridgeman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAMHD1-dependent retroviral control and escape in mice."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2013.163"}], "href": "https://doi.org/10.1038/emboj.2013.163"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23872947"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23872947"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Shuliang Chen, Serena Bonifati, Zhihua Qin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1801213115"}], "href": "https://doi.org/10.1073/pnas.1801213115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29610295"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29610295"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Matilda Rentoft, Kristoffer Lindell, Phong Tran, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1519128113"}], "href": "https://doi.org/10.1073/pnas.1519128113"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27071091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27071091"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Jonathan Maelfait, Anne Bridgeman, Adel Benlahrech, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Restriction by SAMHD1 Limits cGAS/STING-Dependent Innate and Adaptive Immune Responses to HIV-1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2016.07.002"}], "href": "https://doi.org/10.1016/j.celrep.2016.07.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27477283"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27477283"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Sabine Wittmann, Rayk Behrendt, Kristin Eissmann, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of murine SAMHD1 regulates its antiretroviral activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Retrovirology (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/s12977-015-0229-6"}], "href": "https://doi.org/10.1186/s12977-015-0229-6"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26667483"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26667483"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Cristina Miazzi, Paola Ferraro, Giovanna Pontarin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Allosteric regulation of the human and mouse deoxyribonucleotide triphosphohydrolase sterile α-motif/histidine-aspartate domain-containing protein 1 (SAMHD1)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.571091"}], "href": "https://doi.org/10.1074/jbc.M114.571091"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24828500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24828500"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Gregory Berger, Jocelyn Turpin, Stéphanie Cordeil, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Functional analysis of the relationship between Vpx and the restriction factor SAMHD1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.403816"}], "href": "https://doi.org/10.1074/jbc.M112.403816"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23076149"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23076149"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Feifei Wang, Corine St Gelais, Suresh de Silva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Phosphorylation of mouse SAMHD1 regulates its restriction of human immunodeficiency virus type 1 infection, but not murine leukemia virus infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Virology (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.virol.2015.10.024"}], "href": "https://doi.org/10.1016/j.virol.2015.10.024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26580513"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26580513"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Eddy Sanchai Thientosapol, Daniel Bosnjak, Timothy Durack, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAMHD1 enhances immunoglobulin hypermutation by promoting transversion mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1719771115"}], "href": "https://doi.org/10.1073/pnas.1719771115"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29669924"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29669924"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Nicolin Bloch, Sabine Gläsker, Poojitha Sitaram, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Highly Active Isoform of Lentivirus Restriction Factor SAMHD1 in Mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.743740"}], "href": "https://doi.org/10.1074/jbc.M116.743740"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27920203"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27920203"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Tamara Davenne, Jenny Klintman, Sushma Sharma, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Rep (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.celrep.2020.107640"}], "href": "https://doi.org/10.1016/j.celrep.2020.107640"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32402273"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32402273"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Tina Schumann, Santiago Costas Ramon, Nadja Schubert, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Exp Med (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1084/jem.20220829"}], "href": "https://doi.org/10.1084/jem.20220829"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36346347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36346347"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Lorena Valverde-Estrella, Martí López-Serrat, Guillem Sánchez-Sànchez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Induction of Samhd1 by interferon gamma and lipopolysaccharide in murine macrophages requires IRF1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Immunol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/eji.201948491"}], "href": "https://doi.org/10.1002/eji.201948491"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32270872"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32270872"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Bowen Xu, Qianyi Sui, Han Hu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAMHD1 Attenuates Acute Inflammation by Maintaining Mitochondrial Function in Macrophages via Interaction with VDAC1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Mol Sci (2023)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3390/ijms24097888"}], "href": "https://doi.org/10.3390/ijms24097888"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "37175593"}], "href": "https://pubmed.ncbi.nlm.nih.gov/37175593"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "BradleyS Barrett, David H Nguyen, Joella Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SAMHD1 Promotes the Antiretroviral Adaptive Immune Response in Mice Exposed to Lipopolysaccharide."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.2001389"}], "href": "https://doi.org/10.4049/jimmunol.2001389"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34893529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34893529"}]}]}]}