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MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by 2 Preserving Mitochondrial Integrity

ABSTRACT: MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by 2 Preserving Mitochondrial Integrity

PROVIDER: PRJNA1242734 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32881000_1.fastq.gz	Fastqsanger.gz
	SRR32881000_2.fastq.gz	Fastqsanger.gz
	SRR32881001_1.fastq.gz	Fastqsanger.gz
	SRR32881001_2.fastq.gz	Fastqsanger.gz
	SRR32881002_1.fastq.gz	Fastqsanger.gz

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MAVS Orchestrates a Potent IFN-independent Antiviral Immunity by 2 Preserving Mitochondrial Integrity

Project description:Viruses target mitochondria, critical for antiviral defense and metabolism, to evade immunity. While mitochondrial antiviral-signaling protein (MAVS) is known for its regulation of type I interferon (IFN) signaling, we discover that its overarching primary role is safeguarding mitochondrial integrity against virus- and toxin-induced mitophagy. This function is critical in enacting a potent, IFN/NF-κB-independent antiviral response. Using SARS-CoV-2 (CoV-2) infection model, where disruption of MAVS aggregation and induction of mitophagy were observed, we demonstrate that functional MAVS prevents CoV-2-induced mitophagy and restricts viral replication without engaging type I or III interferon (IFN), and NF-κB pathways. Employing MAVS-knockout and MAVS:IFNAR1 double-knockout cells, and inhibition studies, our results further establish MAVS as a critical protector against virus- and chemical mitotoxin-induced mitophagy. Loss of MAVS results in increased mitochondrial membrane depolarization, reduced oxidative potential, and increased PINK1-dependent mitophagy leading to elevated viral replication-all reversed by MAVS supplementation. The IFN-independent antiviral immunity generated by MAVS-driven mitochondrial safeguarding conferred robust protection against mitophagy-inducing viruses, such as CoV-2 and JEV, but not DENV, which does not trigger mitophagy. By facilitating the mitochondrial integrity, MAVS governs the overall innate antiviral immunity- integrating IFN-dependent and IFN-independent mechanisms- and energy metabolism in the host cells. Thus, the regulation of these central functions makes MAVS a prime target for subverting host defenses and cellular energy homeostasis. These insights underscoring MAVS’s wider role in sustaining mitochondrial homeostasis positions it as a promising target for antiviral strategies.

2025-04-30 | GSE293066 | GEO

Cellular RNA interacts with MAVS to promote antiviral signaling

Project description:Immune signaling needs to be well-regulated to promote clearance of pathogens, while preventing aberrant inflammation. Interferons (IFNs) and antiviral genes are activated by the detection of viral RNA by RIG-I-like receptors (RLRs). Signal transduction downstream of RLRs proceeds through a multiprotein complex organized around the central adaptor protein MAVS. While protein-protein interactions and post-translational modifications are critical for the formation of the MAVS signalosome, whether RNA play a role in organizing these platforms is largely unknown. RNA can modulate protein complex function by allosteric regulation or by serving as a molecular guide or scaffold. We have found that MAVS directly interacts with the 3’ untranslated regions of cellular mRNAs through its central intrinsically disordered domain. Eliminating RNA by RNase treatment disrupts the MAVS signalosome and inhibits phosphorylation of the transcription factor IRF3. These findings support the hypothesis that RNA molecules scaffold the MAVS signaling platform to induce IFNs. Indeed, RNase treatment alters interactions between MAVS and newly identified regulators of RLR signaling. Together, this work uncovers a function for cellular RNA in promoting signaling through MAVS and highlights a generalizable principle of RNA regulatory control of cytoplasmic immune signaling complexes.

2025-03-19 | GSE244000 | GEO

Targeting APT2 improves MAVS palmitoylation and antiviral innate immunity

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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MAVS positively regulates mitochondrial integrity and metabolic fitness in antigen receptor-activated B cells

Project description:The role of mitochondrial homeostatic control in the metabolic remodeling associated with antigen receptor stimulation in B cells remains incompletely defined. Here we report that the mitochondrial antiviral signaling (MAVS) adaptor protein is involved in B cell receptor (BCR) initiated cellular proliferation and prolonged survival. MAVS is well known as a mitochondrial tethered signaling adaptor for sensing viral double-stranded RNA and type I interferon inducer. The role of MAVS downstream of BCR stimulation was recognized in absence of interferon, suggesting a new pathway for MAVS activation that is independent of viral infection. Mitochondria of BCR-activated MAVS-deficient B cells exhibited a damaged phenotype including disrupted mitochondrial morphology, excess mitophagy and the temporal progressive blunting of mitochondrial oxidative capacity with mitochondrial hyperpolarization and cell death. Co-stimulation with anti-CD40, in addition to BCR stimulation, corrected the proliferative gap between MAVS-deficient and -sufficient B cells; however, mitochondrial structural defects and functionality were only partially restored. Our data reveal a previously unrecognized role of MAVS in controlling mitochondrial homeostasis in response to BCR initiated B cell proliferation.

2023-07-26 | GSE228413 | GEO

PHF2 maintains neural progenitor genome stability by preserving pericentric heterochromatin integrity

Project description:PHF2 maintains neural progenitor genome stability by preserving pericentric heterochromatin integrity

| PRJNA1013331 | ENA

MAVI1, an Endoplasmic Reticulum-localized Microprotein, Suppresses Antiviral Innate Immune Response by Targeting MAVS on Mitochondrion

Project description:Pattern recognition receptors (PRRs)-mediated innate immune responses are critical for host defense against microbial pathogens including RNA/DNA viruses. A growing number of coding genes and genes originally defined as non-coding RNAs (ncRNAs) are found to encode short peptides or proteins, named microproteins. However, the landscape of microproteins in responsive to virus infection and the functions of these microproteins remain uncharacterized. Here, we systematically identified microproteins, both from coding and non-coding genes, that are responsive to Vesicular Stomatitis Virus (VSV) infection. Among which, a highly conserved, endoplasmic reticulum (ER) membrane-localized microprotein, , MAVI1 (microprotein in antiviral immunity 1), was found to interact with mitochondrial localized MAVS protein, inhibiting the aggregation of MAVS and the activation of downstream type I interferon (IFN) signaling pathway. The critical role of MAVI1 was highlighted that viral infection was significantly attenuated and survival rate was significantly increased in Mavi1 knockout mice in vivo. A peptide inhibitor targeting the interaction between MAVI1 and MAVS is potent in activating the type I IFN signaling and defending viral infection both in vitro and in vivo. Our findings uncovered that microproteins could play critical roles in regulating antiviral innate immune responses via cross-organelle interaction, and targeting microproteins might represent a potential therapeutic avenue for treating viral infection in clinic.

2024-02-15 | GSE221218 | GEO

MAVS positively regulates mitochondrial integrity and metabolic fitness in antigen receptor-activated B cells

Project description:MAVS positively regulates mitochondrial integrity and metabolic fitness in antigen receptor-activated B cells

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