Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies

Annual Review of Immunology, Год журнала: 2019, Номер 37(1), С. 247 - 267

Опубликована: Янв. 11, 2019

Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon-mediated antiviral response triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., fundamental requirement to reliably differentiate self-nucleic from nonself acids. We suggest group Mendelian inborn errors immunity referred as interferonopathies relate breakdown self/nonself discrimination, associated mutant genotypes involving molecules playing direct or indirect roles in acid signaling. This perspective begs question sources self-derived drive inappropriate immune response. Resolving will provide insights into tolerance, signaling, complex autoinflammatory disease states. Here we develop these ideas, discussing within broader framework acid-driven inflammation.

Язык: Английский

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IFI16 Targets the Transcription Factor Sp1 to Suppress HIV-1 Transcription and Latency Reactivation

Cell Host & Microbe, Год журнала: 2019, Номер 25(6), С. 858 - 872.e13

Опубликована: Июнь 1, 2019

Язык: Английский

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Diseases of the nERVous system: retrotransposon activity in neurodegenerative disease

Mobile DNA, Год журнала: 2019, Номер 10(1)

Опубликована: Июль 26, 2019

Transposable Elements (TEs) are mobile genetic elements whose sequences constitute nearly half of the human genome. Each TE copy can be present in hundreds to thousands locations within genome, complicating and genomic studies these highly repetitive sequences. The recent development better tools for evaluating derived has enabled an increasing appreciation contribution TEs disease. While some have contributed novel beneficial host functions, this review will summarize evidence detrimental activity neurodegenerative disorders. Much pathogenicity implicates endogenous retroviruses (ERVs), a subset that entered genome by retroviral infections germline cells our evolutionary ancestors since been passed down as substantial fraction Human specific ERVs (HERVs) represent youngest thus presumed retain greater function resultant pathogenic potential.

Язык: Английский

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SAMHD1 Functions and Human Diseases

Viruses, Год журнала: 2020, Номер 12(4), С. 382 - 382

Опубликована: Март 31, 2020

Deoxynucleoside triphosphate (dNTP) molecules are essential for the replication and maintenance of genomic information in both cells a variety viral pathogens. While process dNTP biosynthesis by cellular enzymes, such as ribonucleotide reductase (RNR) thymidine kinase (TK), has been extensively investigated, negative regulatory mechanism pools was recently found to involve sterile alpha motif (SAM) domain histidine-aspartate (HD) domain-containing protein 1, SAMHD1. When active, triphosphohydrolase activity SAMHD1 degrades dNTPs into their 2'-deoxynucleoside (dN) subparts, steadily depleting intercellular pools. The differential expression levels activation states various cell types contributes unique that either aid (i.e., dividing T cells) or restrict nondividing macrophages) consumes dNTPs. Genetic mutations induce rare inflammatory encephalopathy called Aicardi-Goutières syndrome (AGS), which phenotypically resembles infection. Recent publications have identified diverse roles double-stranded break repair, genome stability, stress response through interferon signaling. Finally, series were also reported cancer while why is mutated these remains investigated. Here, we reviewed studies begun illuminating highly virology, immunology, biology.

Язык: Английский

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Sensing of transposable elements by the antiviral innate immune system

RNA, Год журнала: 2021, Номер 27(7), С. 735 - 752

Опубликована: Апрель 22, 2021

Around half of the genomes in mammals are composed transposable elements (TEs) such as DNA transposons and retrotransposons. Several mechanisms have evolved to prevent their activity detrimental impact insertional mutagenesis. Despite these potentially negative effects, TEs essential drivers evolution, certain settings, beneficial hosts. For instance, rewired antiviral gene regulatory network required for early embryonic development. However, due structural similarities between TE-derived viral nucleic acids, cells can misidentify invading viruses trigger major innate immune pathway, type I interferon (IFN) response. This review will focus on different settings which role TE-mediated IFN activation has been documented, including cancer senescence. Importantly, may also play a causative development complex autoimmune diseases characterized by constitutive activation. All observations suggest presence strong but opposing forces driving coevolution defense. A better biological understanding TE replicative cycle well acid sensing provide insights into how two processes interact help design strategies treat human aberrant expression and/or

Язык: Английский

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Repetitive elements in aging and neurodegeneration

Trends in Genetics, Год журнала: 2023, Номер 39(5), С. 381 - 400

Опубликована: Март 17, 2023

Язык: Английский

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

Nature Communications, Год журнала: 2025, Номер 16(1)

Опубликована: Март 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

Язык: Английский

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L1 retrotransposition in the soma: a field jumping ahead

Mobile DNA, Год журнала: 2018, Номер 9(1)

Опубликована: Июль 7, 2018

Retrotransposons are transposable elements (TEs) capable of "jumping" in germ, embryonic and tumor cells and, as is now clearly established, the neuronal lineage. Mosaic TE insertions form part a broader landscape somatic genome variation hold significant potential to generate phenotypic diversity, brain elsewhere. At present, LINE-1 (L1) retrotransposon family appears be most active autonomous mammals, based on experimental data obtained from disease-causing L1 mutations, engineered reporter systems tested cultured transgenic rodents, single-cell genomic analyses. However, biological consequences almost all identified thus far remain unknown. In this review, we briefly summarize current state-of-the-art field, including estimates retrotransposition rate neurons. We bring forward hypothesis that an extensive subset retrotransposition-competent L1s may de-repressed mobile soma but largely inactive germline. discuss recent reports non-canonical L1-associated sequence variants propose elevated DNA content reported several neurological disorders predominantly comprise accumulated, unintegrated nucleic acids, rather than insertions. Finally, consider main objectives obstacles going elucidating impact retrotransposition.

Язык: Английский

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

Journal of Clinical Investigation, Год журнала: 2022, Номер 132(16)

Опубликована: Июнь 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.

Язык: Английский

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SAMHD1 Suppression of Antiviral Immune Responses

Trends in Microbiology, Год журнала: 2018, Номер 27(3), С. 254 - 267

Опубликована: Окт. 15, 2018

Язык: Английский

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