scholarly journals Viperin interacts with PEX19 to mediate peroxisomal augmentation of the innate antiviral response

2021 ◽  
Vol 4 (7) ◽  
pp. e202000915
Author(s):  
Onruedee Khantisitthiporn ◽  
Byron Shue ◽  
Nicholas S Eyre ◽  
Colt W Nash ◽  
Lynne Turnbull ◽  
...  
Keyword(s):  
Cellular Response ◽  
Close Association ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Binding Partner ◽  
Adapter Molecule ◽  
Innate Antiviral Response ◽  
Mitochondrial Antiviral Signaling ◽  
Antiviral Innate Immunity ◽  
Mitochondrial Antiviral Signaling Protein

Peroxisomes are recognized as significant platforms for the activation of antiviral innate immunity where stimulation of the key adapter molecule mitochondrial antiviral signaling protein (MAVS) within the RIG-I like receptor (RLR) pathway culminates in the up-regulation of hundreds of ISGs, some of which drive augmentation of multiple innate sensing pathways. However, whether ISGs can augment peroxisome-driven RLR signaling is currently unknown. Using a proteomics-based screening approach, we identified Pex19 as a binding partner of the ISG viperin. Viperin colocalized with numerous peroxisomal proteins and its interaction with Pex19 was in close association with lipid droplets, another emerging innate signaling platform. Augmentation of the RLR pathway by viperin was lost when Pex19 expression was reduced. Expression of organelle-specific MAVS demonstrated that viperin requires both mitochondria and peroxisome MAVS for optimal induction of IFN-β. These results suggest that viperin is required to enhance the antiviral cellular response with a possible role to position the peroxisome at the mitochondrial/MAM MAVS signaling synapse, furthering our understanding of the importance of multiple organelles driving the innate immune response against viral infection.

scholarly journals Vaccinia Virus Subverts a Mitochondrial Antiviral Signaling Protein-Dependent Innate Immune Response in Keratinocytes through Its Double-Stranded RNA Binding Protein, E3

2008 ◽  
Vol 82 (21) ◽  
pp. 10735-10746 ◽  
Author(s):  
Liang Deng ◽  
Peihong Dai ◽  
Tanvi Parikh ◽  
Hua Cao ◽  
Vijay Bhoj ◽  
...  
Keyword(s):  
Immune Response ◽  
Vaccinia Virus ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Double Stranded Rna ◽  
Signaling Protein ◽  
Dsrna Binding ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACT Skin keratinocytes provide a first line of defense against invading microorganisms in two ways: (i) by acting as a physical barrier to pathogen entry and (ii) by initiating a vigorous innate immune response upon sensing danger signals. How keratinocytes detect virus infections and generate antiviral immune responses is not well understood. Orthopoxviruses are dermatotropic DNA viruses that cause lethal disease in humans. Virulence in animal models depends on the virus-encoded bifunctional Z-DNA/double-stranded RNA (dsRNA)-binding protein E3. Here, we report that infection of mouse primary keratinocytes with a vaccinia ΔE3L mutant virus triggers the production of beta interferon (IFN-β), interleukin-6 (IL-6), CCL4, and CCL5. None of these immune mediators is produced by keratinocytes infected with wild-type vaccinia virus. The dsRNA-binding domain of E3 suffices to prevent activation of the innate immune response. ΔE3L induction of IFN-β, IL-6, CCL4, and CCL5 secretion requires mitochondrial antiviral signaling protein (MAVS; an adaptor for the cytoplasmic viral RNA sensors RIG-I and MDA5) and the transcription factor IRF3. IRF3 phosphorylation is induced in keratinocytes infected with ΔE3L, an event that depends on MAVS. The response of keratinocytes to ΔE3L is unaffected by genetic ablation of Toll-like receptor 3 (TLR3), TRIF, TLR9, and MyD88.

scholarly journals Mitochondrial Antiviral Signaling Protein Plays a Major Role in Induction of the Fish Innate Immune Response against RNA and DNA Viruses

2009 ◽  
Vol 83 (16) ◽  
pp. 7815-7827 ◽  
Author(s):  
Stéphane Biacchesi ◽  
Monique LeBerre ◽  
Annie Lamoureux ◽  
Yoann Louise ◽  
Emilie Lauret ◽  
...  
Keyword(s):  
Immune Response ◽  
Virus Infection ◽  
Innate Immune Response ◽  
Teleost Fish ◽  
Rna Virus ◽  
Innate Immune ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Fish Cells ◽  
Mitochondrial Antiviral Signaling Protein

ABSTRACT Viral infection triggers host innate immune responses through cellular sensor molecules which activate multiple signaling cascades that induce the production of interferons (IFN) and other cytokines. The recent identification of mammalian cytoplasmic viral RNA sensors, such as retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) and their mitochondrial adaptor, the mitochondrial antiviral signaling protein (MAVS), also called IPS-1, VISA, and Cardif, highlights the significance of these molecules in the induction of IFN. Teleost fish also possess a strong IFN system, but nothing is known concerning the RLRs and their downstream adaptor. In this study, we cloned MAVS cDNAs from several fish species (including salmon and zebrafish) and showed that they were orthologs of mammalian MAVS. We demonstrated that overexpression of these mitochondrial proteins in fish cells led to a constitutive induction of IFN and IFN-stimulated genes (ISGs). MAVS-overexpressing cells were almost fully protected against RNA virus infection, with a strong inhibition of both DNA and RNA virus replication (1,000- and 10,000-fold decreases, respectively). Analyses of MAVS deletion mutants showed that both the N-terminal CARD-like and C-terminal transmembrane domains, but not the central proline-rich region, were indispensable for MAVS signaling function. In addition, we cloned the cDNAs encoding a RIG-I-like molecule from salmonid and cyprinid cell lines. Like the case with MAVS, overexpression of RIG-I CARDs in fish cells led to a strong induction of both IFN and ISGs, conferring on fish cells full protection against RNA virus infection. This report provides the first demonstration that teleost fish possess a functional RLR pathway in which MAVS may play a central role in the induction of the innate immune response.

scholarly journals PLA1A Participates in the Antiviral Innate Immune Response by Facilitating the Recruitment of TANK-Binding Kinase 1 to Mitochondria

2018 ◽  
Vol 10 (4) ◽  
pp. 315-327 ◽  
Author(s):  
Xiaoxiao Gao ◽  
Dan Chen ◽  
Xue Hu ◽  
Yuan Zhou ◽  
Yun Wang ◽  
...  
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Kinase Activity ◽  
Adaptor Proteins ◽  
Innate Immune ◽  
Interferon Β ◽  
Antiviral Signaling ◽  
Innate Immune Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

As a key molecule in the antiviral innate immune response, the activation of TANK-binding kinase 1 (TBK1) is under tight regulation. In this report, we identified phosphatidylserine-specific phospholipase PLA1A as a host factor that modulates the TBK1 activation. Knockdown of PLA1A expression suppressed the innate immune signaling induced by RNA viruses, while PLA1A overexpression enhanced the signaling. PLA1A functioned at the TBK1 level of the signaling pathway, as PLA1A silencing blocked TBK1, but not interferon regulatory factor 3 (IRF3) induced interferon-β (IFN-β) promoter activity. The phosphorylation and kinase activity of TBK1 was reduced in PLA1A knockdown cells. Mechanistically, PLA1A was required in TBK1-mitochondrial antiviral signaling protein (MAVS) interactions but not the interactions of TBK1 with other adaptor proteins. Furthermore, PLA1A knockdown reduced the recruitment of TBK1 and IRF3 to mitochondria, concomitant with altered mitochondria morphology.

scholarly journals Negative Regulation of RNF90 on RNA Virus-Triggered Antiviral Immune Responses Targeting MAVS

2021 ◽  
Vol 12 ◽  
Author(s):  
Bo Yang ◽  
Ge Zhang ◽  
Xiao Qin ◽  
Yulu Huang ◽  
Xiaowen Ren ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Immune Responses ◽  
Rna Virus ◽  
Ring Finger ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Antiviral Signaling ◽  
Antiviral Responses ◽  
Mitochondrial Antiviral Signaling ◽  
Antiviral Innate Immunity

The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity.

scholarly journals Innate Immune Nod1/RIP2 Signaling Is Essential for Cardiac Hypertrophy but Requires Mitochondrial Antiviral Signaling Protein for Signal Transductions and Energy Balance

Circulation ◽  
2020 ◽  
Vol 142 (23) ◽  
pp. 2240-2258 ◽  
Author(s):  
Han-Bin Lin ◽  
Kotaro Naito ◽  
Yena Oh ◽  
Gedaliah Farber ◽  
Georges Kanaan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Remodeling ◽  
Innate Immune ◽  
Transverse Aortic Constriction ◽  
Wild Type ◽  
Aortic Constriction ◽  
Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone. Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1 –/– , RIP2 –/– , or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice. Results: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 –/– and RIP2 –/– mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 –/– and RIP2 –/– mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions. Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

scholarly journals N4BP3 Regulates RIG-I-Like Receptor Antiviral Signaling Positively by Targeting Mitochondrial Antiviral Signaling Protein

2021 ◽  
Vol 12 ◽  
Author(s):  
Chen Wang ◽  
Ting Ling ◽  
Ni Zhong ◽  
Liang-Guo Xu
Keyword(s):  
Immune Response ◽  
Innate Immune Response ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Type I ◽  
Antiviral Signaling ◽  
Signaling Protein ◽  
Antiviral Responses ◽  
Mitochondrial Antiviral Signaling ◽  
Mitochondrial Antiviral Signaling Protein

Mitochondrial antiviral signaling protein (MAVS), an adaptor protein, is activated by RIG-I, which is critical for an effective innate immune response to infection by various RNA viruses. Viral infection causes the RIG-I-like receptor (RLR) to recognize pathogen-derived dsRNA and then becomes activated to promote prion-like aggregation and activation of MAVS. Subsequently, through the recruitment of TRAF proteins, MAVS activates two signaling pathways mediated by TBK1-IRF3 and IKK- NF-κb, respectively, and turns on type I interferon and proinflammatory cytokines. This study discovered that NEDD4 binding protein 3 (N4BP3) is a positive regulator of the RLR signaling pathway by targeting MAVS. Overexpression of N4BP3 promoted virus-induced activation of the interferon-β (IFN-β) promoter and interferon-stimulated response element (ISRE). Further experiments showed that knockdown or knockout N4BP3 impaired RIG-I-like receptor (RLR)-mediated innate immune response, induction of downstream antiviral genes, and cellular antiviral responses. We also detected that N4BP3 could accelerate the interaction between MAVS and TRAF2. Related experiments revealed that N4BP3 could facilitate the ubiquitination modification of MAVS. These findings suggest that N4BP3 is a critical component of the RIG-I-like receptor (RLR)-mediated innate immune response by targeting MAVS, which also provided insight into the mechanisms of innate antiviral responses.

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