Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 132(16)

Published: June 2, 2022

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency autoimmunity, but mechanistic basis for these outcomes incompletely understood. Here, we identify two immune lineage-dependent consequences inactivation dictated by distinct gene interactions. During T cell development, synthetically lethal downregulation dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity antagonized microenvironmental deoxycytidine. In B lymphocytes macrophages, regulates Toll-like receptor 7 signaling controlling levels its (deoxy)guanosine ligands. Overriding this regulatory mechanism promotes germinal center formation absence exogenous antigen accelerates disease a mouse model autoimmunity. work reveals that one purine metabolism protects against autoimmunity via independent mechanisms operating lineages identifies as potentially novel metabolic checkpoint.

Language: Английский

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Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

The Journal of Experimental Medicine, Journal Year: 2022, Volume and Issue: 220(1)

Published: Nov. 8, 2022

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon–driven inflammatory diseases. In these pathophysiological conditions, the DNA sensor cGAS and IFN production are linked damage. Physiological, tonic, signaling on other hand is essential functionally prime sensing pathways. Here, we show that low-level chronic damage mice lacking Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed a p53-deficient, not mismatch repair-deficient background. Increased did result higher levels interferon. Instead, found interferon response SAMHD1-deficient was driven by MDA5/MAVS pathway required functional priming through pathway. Our work positions upstream tonic Samhd1-deficient highlights an important role physiological innate immune priming.

Language: Английский

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TLR4-Mediated Pathway Triggers Interferon-Independent G0 Arrest and Antiviral SAMHD1 Activity in Macrophages

Cell Reports, Journal Year: 2020, Volume and Issue: 30(12), P. 3972 - 3980.e5

Published: March 1, 2020

Macrophages exist predominantly in two distinct states, G0 and a G1-like state that is accompanied by phosphorylation of SAMHD1 at T592. Here, we demonstrate Toll-like receptor 4 (TLR4) activation can potently induce arrest antiretroviral activity an interferon (IFN)-independent pathway. This pathway requires TLR4 engagement with TRIF, but not involvement TBK1 or IRF3. Exclusive Myd88 activators are unable to trigger dephosphorylation, demonstrating this also Myd88/nuclear factor κB (NF-κB) independent. The p21 upregulation CDK1 depletion, consistent the observed dephosphorylation Furthermore, show knockdown TLR4-activated blocks HIV-1 infection macrophages specifically via SAMHD1. Together, these data mobilize intrinsic cell anti-viral activating prior IFN secretion, thereby highlighting importance cell-cycle regulation as response pathogen-associated danger signals macrophages.

Language: Английский

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Nuclear PYHIN proteins target the host transcription factor Sp1 thereby restricting HIV-1 in human macrophages and CD4+ T cells

PLoS Pathogens, Journal Year: 2020, Volume and Issue: 16(8), P. e1008752 - e1008752

Published: Aug. 6, 2020

Members of the family pyrin and HIN domain containing (PYHIN) proteins play an emerging role in innate immunity. While absent melanoma 2 (AIM2) acts a cytosolic sensor non-self DNA plays key inflammasome assembly, γ-interferon-inducible protein 16 (IFI16) restricts retroviral gene expression by sequestering transcription factor Sp1. Here, we show that remaining two human PYHIN proteins, i.e. myeloid cell nuclear differentiation antigen (MNDA) member 1 (PYHIN1 or IFIX) share this antiretroviral function IFI16. On average, knock-down each these three increased infectious HIV-1 yield from macrophages more than order magnitude. Similarly, IFI16 strongly virus production primary CD4+ T cells. The N-terminal (PYD) plus linker region localization signal (NLS) were generally required sufficient for Sp1 sequestration anti-HIV-1 activity IFI16, MNDA PYHIN1. Replacement AIM2 NLS-containing resulted predominantly conferred direct antiviral to while attenuating its ability form inflammasomes. reverse change caused nuclear-to-cytoplasmic relocalization impaired but did not result assembly. We further Zn-finger is critical interaction with supporting domains compete binding. Finally, found also inhibit Hepatitis B simian vacuolating 40 as well LINE-1 retrotransposon. Altogether, our data PYHIN1 restrict other viral pathogens interfering Sp1-dependent support important

Language: Английский

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The SAMHD1-MX2 axis restricts HIV-1 infection at postviral DNA synthesis

mBio, Journal Year: 2024, Volume and Issue: 15(7)

Published: June 18, 2024

HIV-1 replication is tightly regulated in host cells, and various restriction factors have important roles inhibiting viral replication. SAMHD1, a well-known factor, suppresses by hydrolyzing intracellular dNTPs, thereby limiting the synthesis of cDNA quiescent cells. In this study, we revealed an additional distinct mechanism SAMHD1 inhibition during postviral stage. Using immunoprecipitation mass spectrometry analysis, demonstrated interaction between MX2/MxB, interferon-induced antiviral factor that inhibits nuclear import. The disruption endogenous MX2 expression significantly weakened ability to inhibit HIV-1. crucial region within binds has been identified. Notably, found can act as sensor recognizes incoming core, subsequently delivering it molecular trap formed MX2, blocking entry core structure. mutants unable recognize showed substantial decrease activity. Certain mutations capsids confer resistance while maintaining susceptibility suppression SAMHD1-MX2 axis. Overall, our study identifies intriguing pattern wherein two factors, collaborate establish alternative deviating from their actions. These findings provide valuable insight into complex immune defense networks against exogenous infections implications for development targeted anti-HIV therapeutics.

Language: Английский

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Keratin-72 restricts HIV-1 infection in resting CD4+ T cells by sequestering capsids in intermediate filaments

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: March 27, 2025

The accessory protein Vpx from the red-capped mangabey or mandrill SIV (SIVrcm/mnd-2) lineage has been reported to increase HIV-1 infection in resting CD4+ T cells without affecting SAMHD1, a known target of infection. This indicates that Vpx, addition circumvents other restriction factors for lentiviruses. To identify potential factors, this study examined cellular proteins interacting with Vpxrcm and found keratin-72 (KRT72), an intermediate filament (IF) expressed cells, is host antiviral factor targeted by Vpx. Vpxrcm/mnd-2 lineages could strongly promote KRT72 degradation, resulting increased cells. We discovered restricts replication sequestering incoming capsids cytoplasmic IFs. With KRT72, capsid cores become attached IFs, their trafficking toward nucleus inhibited. In contrast, are transported nucleus, leading high levels integrated DNA. Thus, Vpx-counteracted binds restricting inefficient due factors. Here, authors show filament, thereby

Language: Английский

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Novel and emerging treatments for Aicardi-Goutières syndrome

Expert Review of Clinical Immunology, Journal Year: 2019, Volume and Issue: 16(2), P. 189 - 198

Published: Dec. 19, 2019

Introduction: Aicardi-Goutières syndrome (AGS) is the prototype of type I interferonopathies, a new heterogeneous group autoinflammatory disorders in which interferon plays pivotal role. The disease usually manifests itself during infancy, primarily affecting brain and skin, characterized by cerebrospinal fluid chronic lymphocytosis raised levels interferon-alpha cardinal neuroradiological features: cerebral calcification, leukoencephalopathy atrophy. Recently many aspects pathogenesis AGS have been clarified, making it possible to hypothesize therapeutic strategies.Areas covered: We here review recent data concerning novel strategies AGS, including use Janus kinase inhibitors, reverse transcriptase anti-IFN-α antibodies, anti-interleukin antimalarial drugs other cGAS inhibitors.Expert opinion: Thanks identification molecular basis its propose for interferonopathies. A number options are now becoming possible, even though their efficacy still be proven. However, spite research advances coming from clinical trials case series, there open questions, urgently need addressed.

Language: Английский

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SAMHD1 … and Viral Ways around It

Viruses, Journal Year: 2021, Volume and Issue: 13(3), P. 395 - 395

Published: March 2, 2021

The SAM and HD domain-containing protein 1 (SAMHD1) is a dNTP triphosphohydrolase that plays crucial role for variety of different cellular functions. Besides balancing intracellular concentrations, facilitating DNA damage repair, dampening excessive immune responses, SAMHD1 has been shown to act as major restriction factor against various virus species. In addition its well-described activity retroviruses such HIV-1, identified reduce the infectivity viruses herpesviruses CMV EBV, poxvirus VACV, or hepadnavirus HBV. While some are efficiently restricted by SAMHD1, others have developed evasion mechanisms antagonize antiviral SAMHD1. Within this review, we summarize functions highlight countermeasures evolved neutralize

Language: Английский

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Attenuation of reverse transcriptase facilitates SAMHD1 restriction of HIV-1 in cycling cells

Retrovirology, Journal Year: 2023, Volume and Issue: 20(1)

Published: May 1, 2023

Abstract Background SAMHD1 is a deoxynucleotide triphosphohydrolase that restricts replication of HIV-1 in differentiated leucocytes. not restricted cycling cells and it has been proposed this due to phosphorylation at T592 these inactivating the enzymatic activity. To distinguish between theories for how but cells, we analysed effects substitutions on restriction dNTP levels both as well tetramer stability activity vitro. Results We first showed was nuclease then characterised panel mutants divided them into three classes. found subset lost their ability restrict which generally corresponded with decrease and/or Interestingly, no were able WT despite being regulated by retaining hydrolyse dNTPs. Lowering addition hydroxyurea did give rise restriction. Compellingly however, RT reduced affinity dNTPs significantly wild-type mutant U937 Jurkat T-cells. Restriction correlated reverse transcription levels. Conclusions Altogether, amino acid residue 592 strong effect formation and, although simple “on/off” switch, does correlate cells. However, preventing lowering adding enough restore Nonetheless, dNTPs, mediated observe time active capable inhibiting if reduced. This suggests very high prevents

Language: Английский

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Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features

Pediatric Neurology, Journal Year: 2020, Volume and Issue: 115, P. 1 - 6

Published: Nov. 2, 2020

Language: Английский

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