SAMHD1 Suppression of Antiviral Immune Responses

Chen, Shuliang; Bonifati, Serena; Qin, Zhihua; Gelais, Corine St.; Wu, Li

doi:10.1016/j.tim.2018.09.009

Cited by 37 publications

(33 citation statements)

References 115 publications

(140 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this context, the fact that SAMHD1-mediated restriction of exogenous DNA expression does not involve interferon may be additionally beneficial and protects the host from frequent stimulation by interferons. In fact, SAMHD1 has been reported to prevent type I interferon induction [1,10,11]. On the other hand, SAMHD1 expression can be stimulated by interferons [5,44], which might reflect a complexed crosstalk between interferon-dependent and -independent pathways that restrict exogenous DNA.…”

Section: Discussionmentioning

confidence: 99%

“…SAMHD1 (Sterile Alpha Motif and Histidine-aspartate Domain containing protein 1) is expressed in both cycling and noncycling cells, and has been documented as a host restriction factor in the intrinsic antiviral immune system [1]. It possesses a triphosphohydrolase activity that catalyzes the conversion of deoxyribonucleoside triphosphates (dNTP) to deoxyribonucleosides (dN) and triphosphates [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Restriction of exogenous DNA expression by SAMHD1

Fang

et al. 2020

Science Bulletin

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Restriction of exogenous DNA expression by SAMHD1

Fang

et al. 2020

Science Bulletin

View full text Add to dashboard Cite

“…More recently, it was also found that SAMHD1 is a key regulator in innate immune sensing [72][73][74]. SAMHD1 can prevent the cytosolic accumulation of ssDNA by promoting the degradation of nascent DNA at stalled replication forks, which may escape the nucleus during mitosis, thereby limiting innate immune sensing by cGAS [73]. Another study reported that SAMHD1 is able to directly interact with the inhibitor-κB kinase ε (IKKε) and IRF7 to suppress the innate immune response by reducing IKKε-mediated IRF7 phosphorylation [72,74].…”

Section: Innate Control Of Cytoplasmic Dna Accumulationmentioning

confidence: 99%

“…Initially, SAMHD1 was discovered as a restriction factor that prevents HIV-1 reverse transcription through depletion of cellular dNTPs in myeloid cells [18,19]. More recently, it was also found that SAMHD1 is a key regulator in innate immune sensing [72][73][74]. SAMHD1 can prevent the cytosolic accumulation of ssDNA by promoting the degradation of nascent DNA at stalled replication forks, which may escape the nucleus during mitosis, thereby limiting innate immune sensing by cGAS [73].…”

Section: Innate Control Of Cytoplasmic Dna Accumulationmentioning

confidence: 99%

Sensor Sensibility—HIV-1 and the Innate Immune Response

Yin

Langer

Zhang

et al. 2020

Cells

View full text Add to dashboard Cite

Innate immunity represents the human immune system’s first line of defense against a pathogenic intruder and is initiated by the recognition of conserved molecular structures known as pathogen-associated molecular patterns (PAMPs) by specialized cellular sensors, called pattern recognition receptors (PRRs). Human immunodeficiency virus type 1 (HIV-1) is a unique human RNA virus that causes acquired immunodeficiency syndrome (AIDS) in infected individuals. During the replication cycle, HIV-1 undergoes reverse transcription of its RNA genome and integrates the resulting DNA into the human genome. Subsequently, transcription of the integrated provirus results in production of new virions and spreading infection of the virus. Throughout the viral replication cycle, numerous nucleic acid derived PAMPs can be recognized by a diverse set of innate immune sensors in infected cells. However, HIV-1 has evolved efficient strategies to evade or counteract this immune surveillance and the downstream responses. Understanding the molecular underpinnings of the concerted actions of the innate immune system, as well as the corresponding viral evasion mechanisms during infection, is critical to understanding HIV-1 transmission and pathogenesis, and may provide important guidance for the design of appropriate adjuvant and vaccine strategies. Here, we summarize current knowledge of the molecular basis for sensing HIV-1 in human cells, including CD4+ T cells, dendritic cells, and macrophages. Furthermore, we discuss the underlying mechanisms by which innate sensing is regulated, and describe the strategies developed by HIV-1 to evade sensing and immune responses.

show abstract

“…SAMHD1 is a triphosphohydrolase (dNTPase) enzyme, which regulates intracellular levels of dNTPs and acts as an intrinsic immune response factor (11, 12). To function as a dNTPase, the protein forms a homo-tetramer, which is destabilized by phosphorylation.…”

Section: Introductionmentioning

confidence: 99%

SAMHD1 regulates human papillomavirus 16 induced cell proliferation and viral replication during differentiation of oral keratinocytes

Morgan

James

Prabhakar

et al. 2019

Preprint

View full text Add to dashboard Cite

4Human papillomaviruses induce a host of anogenital cancers, and also oropharyngeal cancer 5 (HPV+OPC); HPV16 is causative in around 90% of HPV+OPC. Using TERT immortalized 6 "normal" oral keratinocytes (NOKs) we have identified significant host gene reprogramming by 7 HPV16 (NOKs+HPV16), and demonstrated that NOKs+HPV16 support late stages of the viral life 8 cycle. Expression of the cellular dNTPase and homologous recombination factor SAMHD1 is 9 transcriptionally regulated by HPV16 in NOKs, and here we demonstrate that E6 and E7 regulate 10 expression of SAMHD1 at the transcriptional and post-transcriptional levels. CRISPR/Cas9 11 removal of SAMHD1 from NOKs and NOKs+HPV16 demonstrate that SAMHD1 controls cell 12 proliferation of NOKs only in the presence of HPV16; deletion of SAMHD1 promotes hyper-13 proliferation of NOKs+HPV16 cells in organotypic raft cultures but has no effect on NOKs. Viral 14 replication is also elevated in the absence of SAMHD1. This new system has allowed us to identify 15 a specific interaction between SAMHD1 and HPV16 that regulates host cell proliferation and viral 16 replication; such studies are problematic in non-immortalized primary oral keratinocytes due to 17 their limited lifespan. To confirm the relevance of our results we repeated the analysis with human 18 tonsil keratinocytes immortalized by HPV16 (HTK16) and observe the same hyper-proliferative 19 phenotype following CRISPR/Cas9 editing of SAMHD1. Identical results were obtained with three 20 independent CRISPR/Cas9 guide RNAs. The isogenic pairing of NOKs with NOKs+HPV16, 21 combined with HTK16, presents a unique system to identify host genes whose products 22 functionally interact with HPV16 to regulate host cellular growth in oral keratinocytes. 23 Importance 24Head and neck cancer is the sixth most common cancer worldwide. The incidence of HPV+OPC 25 has been rising steadily since the 1970s and has recently reached epidemic proportions, 26 according to the WHO. Upwards of 70% of the 600,000 new OPC cases per year are HPV 27 positive, with high-risk type 16 present in 90% of those incidences. A better understanding of the 28 viral life cycle will facilitate the development of novel therapeutics to combat this ongoing 29 3 epidemic, as well as other HPV positive cancers. Here we present a unique oral keratinocyte 30 model to identify host proteins that specifically interact with HPV16. Using this system, we report 31 that a cellular gene, SAMHD1, is regulated by HPV16 at the RNA and protein level in oral 32 keratinocytes. Elimination of SAMHD1 from these cells using CRISPR/Cas9 editing promotes 33 enhanced cellular proliferation by HPV16 in oral keratinocytes and elevated viral replication, but 34 not in keratinocytes that do not have HPV16. Our study demonstrates a specific intricate interplay 35 between HPV16 and SAMHD1 during the viral life cycle and establishes a unique model system 36 to assist exploring host factors critical for HPV pathogenesis. 37 38

show abstract

SAMHD1 Suppression of Antiviral Immune Responses

Cited by 37 publications

References 115 publications

Restriction of exogenous DNA expression by SAMHD1

Restriction of exogenous DNA expression by SAMHD1

Sensor Sensibility—HIV-1 and the Innate Immune Response

SAMHD1 regulates human papillomavirus 16 induced cell proliferation and viral replication during differentiation of oral keratinocytes

Contact Info

Product

Resources

About