TRIM8 is required for virus-induced IFN response in human plasmacytoid dendritic cells

Maarifi, Ghizlane; Smith, Nikaïa; Maillet, Sarah; Moncorgé, Olivier; Chamontin, Célia; Edouard, Joanne; Sohm, Frédéric; Blanchet, Fabien P.; Herbeuval, Jean-Philippe; Lutfalla, Georges; Levraud, Jean‐Pierre; Arhel, Nathalie J.; Nisole, Sébastien

doi:10.1126/sciadv.aax3511

Cited by 47 publications

(36 citation statements)

References 57 publications

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“…The pathophysiological role of DCs in viral infection and influenza virus in particular has been studied comprehensively in rodents and human cell culture experiments (35)(36)(37)(38). DCs form a highly developed network within or below the epithelial layer consisting of different DC subtypes.…”

Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Affects Dendritic Cell Populations, Epithelial Barrier Function, and the Immune Response to Viral Infection With H1N1

et al. 2020

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Smokers with apparently "healthy" lungs suffer from more severe and frequent viral respiratory infections, but the mechanisms underlying this observation are still unclear. Epithelial cells and dendritic cells (DC) form the first line of defense against inhaled noxes such as smoke or viruses. We therefore aimed to obtain insight into how cigarette smoke affects DCs and epithelial cells and how this influences the response to viral infection. Female C57BL/6J mice were exposed to cigarette smoke (CS) for 1 h daily for 24 days and then challenged i.n. with the viral mimic and Toll-like receptor 3 (TLR3) ligand poly (I:C) after the last exposure. DC subpopulations were analyzed 24 h later in whole lung homogenates by flow cytometry. Calu-3 cells or human precision-cut lung slices (PCLS) cultured at air-liquid interface were exposed to CS or air and subsequently inoculated with influenza H1N1. At 48 h post infection cytokines were analyzed by multiplex technology. Cytotoxic effects were measured by release of lactate dehydrogenase (LDH) and confocal imaging. In Calu-3 cells the trans-epithelial electrical resistance (TEER) was assessed. Smoke exposure of mice increased numbers of inflammatory and plasmacytoid DCs in lung tissue. Additional poly (I:C) challenge further increased the population of inflammatory DCs and conventional DCs, especially CD11b + cDCs. Smoke exposure led to a loss of the barrier function in Calu-3 cells, which was further exaggerated by additional influenza H1N1 infection. Influenza H1N1-induced secretion of antiviral cytokines (IFN-α2a, IFN-λ, interferon-γ-induced protein 10 [IP-10]), pro-inflammatory cytokine IL-6, as well as T cell-associated cytokines (e.g., I-TAC) were completely suppressed in both Calu-3 cells and human PCLS after smoke exposure. In summary, cigarette smoke exposure increased the number of inflammatory DCs in the lung and disrupted epithelial barrier functions, both of which was further enhanced Danov et al. Smoking and Antiviral Defense by viral stimulation. Additionally, the antiviral immune response to influenza H1N1 was strongly suppressed by smoke. These data suggest that smoke impairs protective innate mechanisms in the lung, which could be responsible for the increased susceptibility to viral infections in "healthy" smokers.

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Section: Discussionmentioning

confidence: 99%

Cigarette Smoke Affects Dendritic Cell Populations, Epithelial Barrier Function, and the Immune Response to Viral Infection With H1N1

et al. 2020

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“…TRIM4 mediates K63-linked polyubiquitination of RIG-I to positively regulate RIG-I-mediated IFN induction [74,75]. TRIM8 has recently been identified as a modulator of innate signaling in plasmacytoid dendritic cells (pDCs), by protecting IRF7 from proteasomal degradation in an E3-Ub ligase-independent manner [76]. On the other hand, TRIM65 has a role in MDA5 K63-linked polyubiquitination by promoting MDA5 activation and oligomerization.…”

Section: Trims In Innate Immunitymentioning

confidence: 99%

TRIM Proteins in Host Defense and Viral Pathogenesis

Giraldo

Hage

Tol

et al. 2020

Curr Clin Micro Rpt

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Purpose of Review Tripartite motif (TRIM) proteins are a large group of E3 ubiquitin ligases involved in different cellular functions. Of special interest are their roles in innate immunity, inflammation, and virus replication. We discuss novel roles of TRIM proteins during virus infections that lead to increased pathogenicity. Recent Findings TRIM proteins regulate different antiviral and inflammatory signaling pathways, mostly by promoting ubiquitination of important factors including pattern recognition receptors, adaptor proteins, kinases, and transcription factors that are involved in type I interferon and NF-κB pathways. Therefore, viruses have developed mechanisms to target TRIMs for immune evasion. New evidence is emerging indicating that viruses have the ability to directly use TRIMs and the ubiquitination process to enhance the viral replication cycle and cause increased pathogenesis. A new report on TRIM7 also highlights the potential pro-viral role of TRIMs via ubiquitination of viral proteins and suggests a novel mechanism by which ubiquitination of virus envelope protein may provide determinants of tissue and species tropism. Summary TRIM proteins have important functions in promoting host defense against virus infection; however, viruses have adapted to evade TRIM-mediated immune responses and can hijack TRIMs to ultimately increase virus pathogenesis. Only by understanding specific TRIM-virus interactions and by using more in vivo approaches can we learn how to harness TRIM function to develop therapeutic approaches to reduce virus pathogenesis.

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“…Cependant, le fait qu'une protéine TRIM8 dépourvue de son domaine RING conserve sa capacité à stabiliser IRF7 phosphorylé (IRF7-P) a rapidement infirmé cette hypothèse. Nous avons alors montré que TRIM8 protège IRF7-P de l'activité de Pin1 (peptidyl-prolyl cis-trans isomerase, NIMA-interacting 1), une enzyme qui induit sa dégradation [10]. Pin1 est une peptidyl-prolyl cis-trans isomérase (PPIase), c'est-à-dire une enzyme qui catalyse l'isomérisation cis-trans de la liaison peptidique en amont d'un résidu proline.…”

Section: La Réponse Interféronunclassified

“…L'étude a été faite sur des pDC purifiées à partir de sang humain, mises en contact avec le VIH ou le virus de la grippe, deux virus à ARN qui sont détectés par la molécule TLR7 présente de manière constitutive dans les endosomes de ces cellules. Cette étude nous a permis d'identifier TRIM20, 22, 28, et 36 comme étant des inhibiteurs de la réponse IFN dans les pDC, tandis que TRIM8 fut l'unique régulateur positif identifié [10]. TRIM8 s'est d'ailleurs avéré être un acteur essentiel de l'activation des pDC, puisqu'en son absence, la production d'IFN par ces cellules est quasiment inexistante, un résultat inattendu que nous avons alors cherché à expliquer.…”

Section: Contrôle De La Réponse Ifn Par Les Protéines Trimunclassified