SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Chen, Shuliang; Bonifati, Serena; Qin, Zhihua; Gelais, Corine St.; Kodigepalli, Karthik M.; Barrett, Bradley S.; Kim, Sun Hee; Antonucci, Jenna M.; Ladner, Katherine J.; Buzovetsky, Olga; Knecht, Kirsten M.; Xiong, Yong; Yount, Jacob S.; Guttridge, Denis C.; Santiago, Mario L.; Wu, Li

doi:10.1073/pnas.1801213115

Cited by 105 publications

(214 citation statements)

References 50 publications

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“…4666) or heatinactivated HIV-1 was used as controls. Heat-inactivated HIV-1 was generated by incubating the virus at 65°C for 1 h as described (45). Activated primary CD4 ϩ T-cells were infected with HIV-1 NL4 -3 (MOI of 1), and cells were harvested at 96 hpi for total RNA extraction using RNAeasy kit (Qiagen).…”

Section: Hiv-1 Infection Assays and Treatment With Heat-inactivated Hmentioning

confidence: 99%

HIV-1 envelope proteins up-regulate N6-methyladenosine levels of cellular RNA independently of viral replication

Tirumuru

2019

Journal of Biological Chemistry

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Edited by Charles E. Samuel N 6 -methyladenosine (m 6 A) modification of HIV-1 RNA regulates viral replication and protein expression. The m 6 A modification is regulated by two groups of cellular proteins named writers and erasers that add or remove m 6 A, respectively. HIV-1 infection of CD4 ؉ T-cells increases m 6 A levels of cellular mRNA, but the underlying mechanism is unknown. Here, we show that HIV-1 infection of CD4 ؉ primary T-cells or Jurkat cells significantly increases m 6 A levels of cellular RNA independently of viral replication. Compared with HIV-1-infected CD4 ؉ T-cells, similar m 6 A up-regulation was detected in total RNA from HIV-1-infected cells treated with a reverse-transcriptase inhibitor or with heat-inactivated HIV-1. Compared with mock controls, significantly increased m 6 A levels were detected in total RNA from Jurkat cells infected by single-cycle HIV-1 pseudotyped with an HIV-1 envelope (Env) glycoprotein, but not with vesicular stomatitis virus glycoprotein G (VSV-G).Overexpression of HIV-1 Env in HEK293T cells did not affect m 6 A levels of cellular RNA, suggesting that de novo synthesis of Env is not required for m 6 A up-regulation. Interestingly, treatment of Jurkat cells with recombinant gp120 of HIV-1 Env significantly increased m 6 A levels of cellular RNA, which was reduced by a gp120-neutralizing antibody. Preincubation of Jurkat cells with a CD4 receptor-neutralizing antibody blocked HIV-1-induced up-regulation of m 6 A levels in cellular RNA. Moreover, HIV-1 infection or gp120 treatment did not alter the protein expression of m 6 A writers and erasers in cells. Our findings suggest that HIV-1 gp120 binding to the CD4 receptor is required for m 6 A up-regulation in cells. . 2 The abbreviations used are: m 6 A, N 6 -methyladenosine; MOI, multiplicity of infection; hpi, hours post-infection; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; NVP, nevirapine; Env, HIV-1 envelope proteins; METTL, methyltransferase-like protein; FTO, fat mass and obesity-associated protein; AlkBH5, AlkB family member 5; MB, methylene blue; sncRNA, small noncoding RNA; sCD4, soluble CD4; NARP, National Institutes of Health AIDS Reagent Program; SSC, saline-sodium citrate.

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Section: Hiv-1 Infection Assays and Treatment With Heat-inactivated Hmentioning

confidence: 99%

HIV-1 envelope proteins up-regulate N6-methyladenosine levels of cellular RNA independently of viral replication

Tirumuru

2019

Journal of Biological Chemistry

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“…The transcription factor NF‐κB plays an important role in regulating the inflammatory response . NF‐κB consists of five proteins, including p65, p50, p52, c‐Rel, and RelB.…”

Section: Introductionmentioning

confidence: 99%

A Novel Quinolyl‐Substituted Analogue of Resveratrol Inhibits LPS‐Induced Inflammatory Responses in Microglial Cells by Blocking the NF‐κB/MAPK Signaling Pathways

Hou

Zhang

et al. 2019

Molecular Nutrition Food Res

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Scope The anti‐neuroinflammatory effect of a novel quinolyl‐substituted analogue of resveratrol (RV01) on lipopolysaccharide (LPS)‐induced microglial activation is investigated, as well as the possible underlying mechanisms. Methods and results Cell viability is measured using an MTT assay. Nitric oxide (NO) release is determined by nitrite assay. The interaction between RV01 and inducible nitric oxide synthase (iNOS) is studied using molecular docking. Free radical scavenging activity and reactive oxygen species (ROS) production are determined by DPPH reduction assay and DCFH‐DA assay. Pretreatment with RV01 (1–30 µm) prior to LPS (1 µg mL–1) stimulation decreased NO release and iNOS expression without observable cytotoxicity. RV01 reduced the mRNA levels and secretion of tumor necrosis factor‐α (TNF‐α) and interleukin‐6 (IL‐6). RV01 also inhibited LPS‐induced ROS production and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. Furthermore, RV01 decreases the protein expression of toll‐like receptor 4 (TLR4) and inhibits the LPS‐induced activation of the mitogen‐activated protein kinase (MAPK) and nuclear transcription factor‐κB (NF‐κB) signaling pathways. Additionally, conditioned medium from microglia co‐treated with LPS and RV01 alleviates the death of SH‐SY5Y cells induced by conditioned medium from activated N9 microglial cells. Lastly, a mouse neuroinflammation model is further used to confirm the effect of RV01 in vivo. Conclusion These results show that RV01 suppresses microglia‐mediated neuroinflammation and protects neurons from inflammatory damage, which indicates that RV01 has great potential as a nutritional preventive strategy for neuroinflammation‐related diseases.

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“…By decreasing the pool of available dNTPs to a level insufficient to support reverse transcription, SAMHD1 was able to restrict a broad range of retroviruses, including HIV-1, during the early reverse transcription step [30,31]. In addition, SAMHD1 might have the ability to modulate antiviral activity by inhibiting the NF-B and interferon pathways [32]. Regarding HTLV-1, Gramberg et al [33] demonstrated that, in macrophages and cycling CD4+ T cells, the virus was not blocked by SAMHD1 and that Tax was produced.…”

Section: Samhd1mentioning

confidence: 99%

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

Prochasson¹,

Jalinot²,

Mocquet³

2020

Preprint

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Before the adaptive immune response is established, retroviruses can be targeted by several cellular host factors at different stages of the viral replication cycle. This intrinsic immunity relies on a large diversity of antiviral processes. In the case of HTLV-1 infection, these active innate host defence mechanisms are debated. Among these mechanisms, we focused on a RNA decay pathway called nonsense-mediated mRNA decay (NMD), which can target multiple viral RNAs, including HTLV-1 unspliced RNA, as it has been recently demonstrated. NMD is a cotranslational process that depends on the RNA helicase UPF1 and regulates the expression of multiple types of host mRNAs. RNA sensitivity to NMD depends on mRNA organization and the ribonucleoprotein (mRNP) composition.HTLV-1 has evolved several means to evade the NMD threat, leading to NMD inhibition. In the early steps of infection, NMD inhibition favours the production of HTLV-1 infectious particles, which may contribute to the survival of the most fit clones despite genome instability; however, its direct longterm impact remains to be investigated.

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SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-κB and interferon pathways

Cited by 105 publications

References 50 publications

HIV-1 envelope proteins up-regulate N6-methyladenosine levels of cellular RNA independently of viral replication

HIV-1 envelope proteins up-regulate N6-methyladenosine levels of cellular RNA independently of viral replication

A Novel Quinolyl‐Substituted Analogue of Resveratrol Inhibits LPS‐Induced Inflammatory Responses in Microglial Cells by Blocking the NF‐κB/MAPK Signaling Pathways

An Antiviral Process Targeting HTLV-1: The Complex Relationship between HTLV-1 and Nonsense-mediated mRNA Decay

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