Mitochondrial DNA-triggered innate immune response: mechanisms and diseases

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(12), С. 1403 - 1412

Опубликована: Ноя. 7, 2023

Abstract Various cellular stress conditions trigger mitochondrial DNA (mtDNA) release from mitochondria into the cytosol. The released mtDNA is sensed by cGAS-MITA/STING pathway, resulting in induced expression of type I interferon and other effector genes. These processes contribute to innate immune response viral infection factors. deregulation these causes autoimmune diseases, inflammatory metabolic disorders cancer. Therefore, pathway a potential target for intervention infectious, diseases as well In this review, we focus on mechanisms underlying mtDNA-triggered activation effects under various physiological pathological conditions, advances development drugs that cGAS MITA/STING.

Язык: Английский

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Physiological functions of RIG-I-like receptors

Immunity, Год журнала: 2024, Номер 57(4), С. 731 - 751

Опубликована: Апрель 1, 2024

Язык: Английский

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Anti-RNApol3-Associated myocarditis: an emerging disease linking autoimmunity and infection

Annals of Intensive Care, Год журнала: 2025, Номер 15(1)

Опубликована: Март 24, 2025

Abstract Background Fulminant myocarditis (FM) is a severe condition primarily triggered by viruses. Anti-RNA polymerase III autoantibodies (RNApol3) which are typically found in patients with systemic sclerosis, have been reported influenza-related FM. Our objective to provide additional insight into RNApol3-associated Methods We retrospectively included all admitted our institution between January 2013 and June 2023 acute positive serum RNApol3. compared their characteristics, etiologies, outcomes those of cohort RNApol3 negative myocarditis. Results Twenty-nine RNApol3-positive patients, comprising 83% females mean age 39 ± 12 years, were this study. Each patient was the intensive care unit at least once 11 (38%) relapsed. Triggers influenza virus 55% SARS-CoV-2 48% cases. The lowest left ventricular ejection fraction 10 [5-10] % highest troponin value 82 [22–360] times ULN. Patients required dobutamine (94%), veno-arterial extracorporeal membrane oxygenation (85%) pericardiocentesis (38%). At last follow-up, 76% still alive, while 7% had undergone cardiac transplantation, 3% assist device. Compared RNApol3-negative cases, associated female gender, fulminant evolution, tamponade, higher likelihood being caused proven viral infection, rate relapse. Conclusion an emerging disease linking autoimmunity infection unique cause acquired, pathogen-specific, organ-specific immunodeficiency. should be screened cases FM, especially young women infected RNA risk FM sclerosis needs further investigation.

Язык: Английский

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The molecular language of RNA 5′ ends: guardians of RNA identity and immunity

RNA, Год журнала: 2024, Номер 30(4), С. 327 - 336

Опубликована: Фев. 7, 2024

RNA caps are deposited at the 5′ end of polymerase II transcripts. This modification regulates several steps gene expression, in addition to marking transcripts as self enable innate immune system distinguish them from uncapped foreign RNAs, including those derived viruses. Specialized sensors, such RIG-I and IFITs, trigger antiviral responses upon recognition cytoplasmic Interestingly, can also be produced by mammalian hosts. For instance, 5′-triphosphate RNAs generated III transcription, tRNAs, Alu or vault RNAs. These have emerged key players immunity, they recognized sensors. Mechanisms that regulate presence 5′-triphosphates, 5′-end dephosphorylation editing, prevent endogenous excessive inflammation. Here, we provide a comprehensive overview complexity cap structures highlighting their roles transcript identity, surveillance, disease.

Язык: Английский

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Feedback loop centered on MAF1 reduces blood–brain barrier damage in sepsis-associated encephalopathy

Cellular & Molecular Biology Letters, Год журнала: 2025, Номер 30(1)

Опубликована: Янв. 20, 2025

Abstract Background A previous study found that MAF1 homolog, a negative regulator of RNA polymerase III ( ), protects the blood–brain barrier (BBB) in sepsis-associated encephalopathy (SAE); however, related molecular mechanisms remain unclear. Subjects and methods In this study, rat sepsis model was constructed using cecum ligation puncture (CLP) method. vitro, brain microvascular endothelial cells astrocytes were stimulated with serum from rats. The loss protein levels leading to cell damage investigated. Results It shown SAE models expressed at low levels. Knockdown Cullin 2 CUL2 ) accumulation protein, attenuated sensor RIG-I/interferon regulatory factor 3 (IRF3) signaling pathway, reduced apoptosis. Furthermore, it increased phosphatase tensin homolog PTEN expression inactivated serine/threonine kinase (AKT)/mechanistic target rapamycin (mTOR) pathway. Interference forkhead box O1 FOXO1 inhibited activated RIG-I/IRF3 while overexpression promoted expression, decreased apoptosis, normalized autophagy. Conclusions These findings demonstrate ubiquitination caused BBB injury SAE. Through loop PTEN/AKT/FOXO1/MAF1, initiated gradual downregulation , which subsequently regulated (Pol III)-dependent transcription played essential roles apoptosis Clinical trial number : not applicable. Graphical

Язык: Английский

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Cellular RNA acts as an antiviral MAVS signalosome scaffold

Trends in Immunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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MDA5 ISGylation is crucial for immune signaling to control viral replication and pathogenesis

Proceedings of the National Academy of Sciences, Год журнала: 2025, Номер 122(14)

Опубликована: Апрель 4, 2025

The posttranslational modification (PTM) of innate immune sensor proteins by ubiquitin or ubiquitin-like is crucial for regulating antiviral host responses. cytoplasmic dsRNA receptor melanoma differentiation-associated protein 5 (MDA5) undergoes several PTMs including ISGylation within its first caspase activation and recruitment domain (CARD), which promotes MDA5 signaling. However, the relevance immunity in an infected organism has been elusive. Here, we generated knock-in mice (MDA5K23R/K43R) two major sites, K23 K43, MDA5, were mutated. Primary cells derived from MDA5K23R/K43R exhibited abrogated endogenous impaired ability to form oligomeric assemblies, leading blunted cytokine responses RNA-agonist stimulation infection with encephalomyocarditis virus (EMCV) West Nile virus. Phenocopying MDA5-/- mice, EMCV displayed increased myocardial injury mortality, elevated viral titers, ablated induction cytokines chemokines compared WT mice. Molecular studies identified human HERC5 (and functional murine homolog HERC6) as primary E3 ligases responsible activation. Taken together, these findings establish importance CARD MDA5-mediated RNA restriction, promoting potential avenues immunomodulatory drug design anti-inflammatory applications.

Язык: Английский

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Viral piracy of host RNA phosphatase DUSP11 by avipoxviruses

PLoS Pathogens, Год журнала: 2025, Номер 21(4), С. e1013101 - e1013101

Опубликована: Апрель 21, 2025

Proper recognition of viral pathogens is an essential part the innate immune response. A common replicative intermediate and chemical signal that cells use to identify presence a triphosphorylated 5’ end (5’ppp) RNA, which activates cytosolic RNA sensor RIG-I initiates downstream antiviral signaling. While 5’pppRNA generated by RNA-dependent polymerases (RdRps) can be potent activator response, endogenous polymerase III (RNAPIII) transcripts retain 5’ppp during transcription induce RIG-I-mediated We have previously shown host triphosphatase dual-specificity phosphatase 11 (DUSP11) act on both RNAs, altering their levels reducing ability activation. Our previous work explored how experimentally altered DUSP11 activity impact activation, prompting further exploration into natural contexts activity. Here, we identified homologs (vDUSP11s) present in some avipoxviruses. Consistent with known functions DUSP11, expression vDUSP11s: 1) reduces RNAPIII transcripts, 2) cell’s sensitivity 5’pppRNA-mediated 3) restores virus infection defects seen absence DUSP11. results context where has been co-opted viruses alter metabolism influence outcome infection.

Язык: Английский

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Innate Immune Recognition of EBV

Current topics in microbiology and immunology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Retrotransposon life cycle and its impacts on cellular responses

RNA Biology, Год журнала: 2024, Номер 21(1), С. 11 - 27

Опубликована: Окт. 13, 2024

Approximately 45% of the human genome is comprised transposable elements (TEs), also known as mobile genetic elements. However, their biological function remains largely unknown. Among them, retrotransposons are particularly abundant, and some copies still capable mobilization within through RNA intermediates. This review focuses on life cycle summarizes regulatory mechanisms impacts cellular processes. Retrotransposons generally epigenetically silenced in somatic cells, but transcriptionally reactivated under certain conditions, such tumorigenesis, development, stress, ageing, potentially leading to instability. We explored dual nature genomic parasites elements, focusing roles diversity innate immunity. Furthermore, we discuss how host factors regulate retrotransposon cDNA intermediates binding, modification, degradation. The interplay between machinery provides insight into complex regulation potential for dysregulation cause aberrant responses inflammation autoimmune diseases.

Язык: Английский

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