Innate triggering and antiviral effector functions of activin A
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA786577 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17143222_1.fastq.gz | Fastqsanger.gz | |||
| SRR17143222_2.fastq.gz | Fastqsanger.gz | |||
| SRR17143223_1.fastq.gz | Fastqsanger.gz | |||
| SRR17143223_2.fastq.gz | Fastqsanger.gz | |||
| SRR17143224_1.fastq.gz | Fastqsanger.gz |
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Project description:Innate immunity serves as the primary defense against viral and microbial infections in humans. Among its components, retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) are well-characterized intracellular pattern-recognition proteins that trigger innate immune responses upon viral infection. However, the precise influence of cellular metabolites, especially fatty acids, on the regulation of RLR-mediated antiviral innate immunity remains largely elusive. Here, through screening a metabolite library, palmitic acid (PA) has been identified as a crucial metabolite responsible for modulating antiviral infections. Mechanistically, PA induces the palmitoylation of MAVS, leading to MAVS aggregation and subsequent activation, thereby enhancing the innate immune response against viral infections. Functionally, the enzyme palmitoyl-transferase ZDHHC24 plays a key role in catalyzing the palmitoylation of MAVS at both C46 and C79 residues, thereby facilitating the transduction of RLR-mediated TBK1-IRF3-IFN signaling pathway, particularly under conditions of PA stimulation or high-fat diet feeding. Conversely, the absence of ZDHHC24 significantly attenuates virus-induced innate immune responses in both cells and mice. Moreover, APT2 counteracts with ZDHHC24 to de-palmitoylate MAVS, thus inhibiting the antiviral response. Consequently, inhibition of APT2 using compounds like ML349 effectively reverses MAVS palmitoylation and activation in response to antiviral infections. These findings underscore the critical role of PA and ZDHHC24 in regulating antiviral innate immunity through MAVS palmitoylation, and suggest potential therapeutic strategies for combating viral infections, such as enhancing PA intake or specifically targeting APT2.
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Project description:The innate immune response is the first line of defense against pathogens, and factors that control this cellular response represent targets for treating both infectious and inflammatory diseases. Here, we reveal a novel role for the human helicase SETX, also previously implicated in amyotrophic lateral sclerosis (ALS4) and ataxia with oculomotor apraxia (AOA2), in controlling the magnitude of the antiviral response. Cells depleted for SETX and AOA2 patient-derived SETX-null cells show increased expression of antiviral mediators in response to infection. Mechanistically, this effect is achieved through SETX-mediated inhibition of RNAPII transcription of antiviral genes, and depends on SETX helicase activity. Our results suggest that SETX helps maintain the delicate balance between controlling viral infection and avoiding the potentially detrimental effects of an excessive antiviral response. More broadly, the observation that SETX can regulate the transcriptional activity of specific genes may have important implications for disorders where SETX function is compromised. A549 cells that were transfected with either control non-targeting or SETX-specific siRNAs were infected with the Influenza A virus (A/PR/8/34(ΔNS1) strain) at a multiplicity of infection (MOI) of 3 for 4 hours. Nuclei were then extracted and used to prepare Global Run-On Sequencing (GRO-seq) libraries.
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Project description:Background: Although tumor-infiltrating T cells represent a favorable prognostic marker for cancer patients, the majority of these cells are rendered with an exhausted phenotype. Hence, there is an unmet need to identify factors which can reverse this dysfunctional profile and restore their anti-tumorigenic potential. Activin-A is a pleiotropic cytokine, exerting a broad range of pro- or anti-inflammatory functions in different disease contexts, including allergic and autoimmune disorders and cancer. Given that activin-A exhibits a profound effect on CD4+ T cells in the airways and is elevated in lung cancer patients, we hypothesized that activin-A can effectively regulate anti-tumor immunity in lung cancer. Methods: To evaluate the effects of activin-A in the context of lung cancer, we utilized the OVA-expressing Lewis Lung Carcinoma mouse model as well as the B16F10 melanoma model of pulmonary metastases. The therapeutic potential of activin-A-treated lung tumor-infiltrating CD4+ T cells was evaluated in adoptive transfer experiments, using CD4-/--tumor bearing mice as recipients. In a reverse approach, we disrupted activin-A signaling on CD4+ T cells using an inducible model of CD4+ T cell-specific knockout of activin-A type I receptor. RNA-Sequencing analysis was performed to assess the transcriptional signature of these cells and the molecular mechanisms which mediate activin-A’s function. In a translational approach, we validated activin-A’s anti-tumorigenic properties using primary human tumor-infiltrating CD4+ T cells from lung cancer patients. Results: Administration of activin-A in lung tumor-bearing mice attenuated disease progression, an effect associated with heightened ratio of infiltrating effector to regulatory CD4+ T cells. Therapeutic transfer of lung tumor-infiltrating activin-A-treated CD4+ T cells, delayed tumor progression in CD4-/- recipients and enhanced T cell-mediated immunity. CD4+ T cells genetically unresponsive to activin-A, failed to elicit effective anti-tumor properties and displayed an exhausted molecular signature governed by the transcription factors Tox and Tox2. Of translational importance, treatment of activin-A on tumor-infiltrating CD4+ T cells from lung cancer patients augmented their immunostimulatory capacity towards autologous CD4+ and CD8+ T cells. Conclusions: In this study, we introduce activin-A as a novel immunomodulatory factor in the lung tumor microenvironment, which bestows exhausted CD4+ T cells with effector properties.
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