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1.
Nat Immunol ; 17(8): 985-96, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27376471

RESUMEN

The activation marker CD69 is expressed by skin γδ T cells. Here we found that CD69 controlled the aryl hydrocarbon receptor (AhR)-dependent secretion of interleukin 22 (IL-22) by γδ T cells, which contributed to the development of psoriasis induced by IL-23. CD69 associated with the aromatic-amino-acid-transporter complex LAT1-CD98 and regulated its surface expression and uptake of L-tryptophan (L-Trp) and the intracellular quantity of L-Trp-derived activators of AhR. In vivo administration of L-Trp, an inhibitor of AhR or IL-22 abrogated the differences between CD69-deficient mice and wild-type mice in skin inflammation. We also observed LAT1-mediated regulation of AhR activation and IL-22 secretion in circulating Vγ9(+) γδ T cells of psoriatic patients. Thus, CD69 serves as a key mediator of the pathogenesis of psoriasis by controlling LAT1-CD98-mediated metabolic cues.


Asunto(s)
Antígenos CD/metabolismo , Antígenos de Diferenciación de Linfocitos T/metabolismo , Lectinas Tipo C/metabolismo , Psoriasis/inmunología , Piel/inmunología , Subgrupos de Linfocitos T/inmunología , Células Th17/inmunología , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+L , Animales , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Células Cultivadas , Endocitosis , Proteína-1 Reguladora de Fusión/metabolismo , Interleucina-23/inmunología , Interleucinas/metabolismo , Lectinas Tipo C/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Hidrocarburo de Aril/metabolismo , Triptófano/metabolismo , Interleucina-22
3.
Trends Immunol ; 39(8): 591-595, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29937401

RESUMEN

Histone deacetylase 6 (HDAC6) acts by enzyme-dependent and -independent mechanisms to regulate diverse cellular processes including autophagy, the ubiquitin proteasome system, and cell migration. HDAC6 also has emerging roles in innate immunity, including pathogen sensing and destruction, thus placing this enzyme at the crossroads of infection and innate immunity.


Asunto(s)
Histona Desacetilasa 6/metabolismo , Infecciones/inmunología , Complejo de la Endopetidasa Proteasomal/metabolismo , Animales , Autofagia , Histona Desacetilasa 6/genética , Humanos , Inmunidad Innata , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , Transducción de Señal
4.
PLoS Pathog ; 13(12): e1006799, 2017 12.
Artículo en Inglés | MEDLINE | ID: mdl-29281743

RESUMEN

Recent evidence on HDAC6 function underlines its role as a key protein in the innate immune response to viral infection. However, whether HDAC6 regulates innate immunity during bacterial infection remains unexplored. To assess the role of HDAC6 in the regulation of defence mechanisms against intracellular bacteria, we used the Listeria monocytogenes (Lm) infection model. Our data show that Hdac6-/- bone marrow-derived dendritic cells (BMDCs) have a higher bacterial load than Hdac6+/+ cells, correlating with weaker induction of IFN-related genes, pro-inflammatory cytokines and nitrite production after bacterial infection. Hdac6-/- BMDCs have a weakened phosphorylation of MAPK signalling in response to Lm infection, suggesting altered Toll-like receptor signalling (TLR). Compared with Hdac6+/+ counterparts, Hdac6-/- GM-CSF-derived and FLT3L-derived dendritic cells show weaker pro-inflammatory cytokine secretion in response to various TLR agonists. Moreover, HDAC6 associates with the TLR-adaptor molecule Myeloid differentiation primary response gene 88 (MyD88), and the absence of HDAC6 seems to diminish the NF-κB induction after TLR stimuli. Hdac6-/- mice display low serum levels of inflammatory cytokine IL-6 and correspondingly an increased survival to a systemic infection with Lm. The impaired bacterial clearance in the absence of HDAC6 appears to be caused by a defect in autophagy. Hence, Hdac6-/- BMDCs accumulate higher levels of the autophagy marker p62 and show defective phagosome-lysosome fusion. These data underline the important function of HDAC6 in dendritic cells not only in bacterial autophagy, but also in the proper activation of TLR signalling. These results thus demonstrate an important regulatory role for HDAC6 in the innate immune response to intracellular bacterial infection.


Asunto(s)
Autofagia/inmunología , Histona Desacetilasa 6/inmunología , Inmunidad Innata , Listeria monocytogenes/inmunología , Listeria monocytogenes/patogenicidad , Receptores Toll-Like/inmunología , Animales , Células Dendríticas/inmunología , Femenino , Histona Desacetilasa 6/deficiencia , Histona Desacetilasa 6/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Interleucina-6/sangre , Listeriosis/enzimología , Listeriosis/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/inmunología , Transducción de Señal/inmunología
5.
Cell Mol Life Sci ; 75(1): 1-19, 2018 01.
Artículo en Inglés | MEDLINE | ID: mdl-29080091

RESUMEN

Extracellular vesicles (EVs) are released by cells to the extracellular environment to mediate inter-cellular communication. Proteins, lipids, nucleic acids and metabolites shuttled in these vesicles modulate specific functions in recipient cells. The enrichment of selected sets of proteins in EVs compared with global cellular levels suggests the existence of specific sorting mechanisms to specify EV loading. Diverse post-translational modifications (PTMs) of proteins participate in the loading of specific elements into EVs. In this review, we offer a perspective on PTMs found in EVs and discuss the specific role of some PTMs, specifically Ubiquitin and Ubiquitin-like modifiers, in exosomal sorting of protein components. The understanding of these mechanisms will provide new strategies for biomedical applications. Examples include the presence of defined PTM marks on EVs as novel biomarkers for the diagnosis and prognosis of certain diseases, or the specific import of immunogenic components into EVs for vaccine generation.


Asunto(s)
Endosomas/metabolismo , Exosomas/metabolismo , Cuerpos Multivesiculares/metabolismo , Procesamiento Proteico-Postraduccional , Proteínas/metabolismo , Animales , Humanos , Lisosomas/metabolismo , Modelos Biológicos , Transporte de Proteínas
6.
J Cell Sci ; 129(7): 1305-1311, 2016 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-26869226

RESUMEN

HDAC6 is a tubulin deacetylase involved in many cellular functions related to cytoskeleton dynamics, including cell migration and autophagy. In addition, HDAC6 affects antigen-dependent CD4(+)T cell activation. In this study, we show that HDAC6 contributes to the cytotoxic function of CD8(+)T cells. Immunization studies revealed defective cytotoxic activity in vivo in the absence of HDAC6. Adoptive transfer of wild-type or Hdac6(-/-)CD8(+)T cells to Rag1(-/-)mice demonstrated specific impairment in CD8(+)T cell responses against vaccinia infection. Mechanistically, HDAC6-deficient cytotoxic T lymphocytes (CTLs) showed defective in vitro cytolytic activity related to altered dynamics of lytic granules, inhibited kinesin-1-dynactin-mediated terminal transport of lytic granules to the immune synapse and deficient exocytosis, but not to target cell recognition, T cell receptor (TCR) activation or interferon (IFN)γ production. Our results establish HDAC6 as an effector of the immune cytotoxic response that acts by affecting the dynamics, transport and secretion of lytic granules by CTLs.


Asunto(s)
Gránulos Citoplasmáticos/metabolismo , Citotoxicidad Inmunológica/inmunología , Histona Desacetilasas/metabolismo , Linfocitos T Citotóxicos/inmunología , Vaccinia/inmunología , Animales , Transporte Biológico/fisiología , Células Cultivadas , Citotoxicidad Inmunológica/genética , Complejo Dinactina/antagonistas & inhibidores , Histona Desacetilasa 6 , Histona Desacetilasas/genética , Interferón gamma/metabolismo , Cinesinas/antagonistas & inhibidores , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
7.
Front Immunol ; 13: 946358, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36131943

RESUMEN

Communication through cell-cell contacts and extracellular vesicles (EVs) enables immune cells to coordinate their responses against diverse types of pathogens. The function exerted by EVs in this context depends on the proteins and nucleic acids loaded into EVs, which elicit specific responses involved in the resolution of infection. Several mechanisms control protein and nucleic acid loading into EVs; in this regard, acetylation has been described as a mechanism of cellular retention during protein sorting to exosomes. HDAC6 is a deacetylase involved in the control of cytoskeleton trafficking, organelle polarity and cell migration, defense against Listeria monocytogenes (Lm) infection and other immune related functions. Here, we show that the protein content of dendritic cells (DCs) and their secreted EVs (DEVs) vary during Lm infection, is enriched in proteins related to antiviral functions compared to non-infected cells and depends on HDAC6 expression. Analyses of the post-translational modifications revealed an alteration of the acetylation and ubiquitination profiles upon Lm infection both in DC lysates and DEVs. Functionally, EVs derived from infected DCs upregulate anti-pathogenic genes (e.g. inflammatory cytokines) in recipient immature DCs, which translated into protection from subsequent infection with vaccinia virus. Interestingly, absence of Listeriolysin O in Lm prevents DEVs from inducing this anti-viral state. In summary, these data underscore a new mechanism of communication between bacteria-infected DC during infection as they alert neighboring, uninfected DCs to promote antiviral responses.


Asunto(s)
Vesículas Extracelulares , Listeria monocytogenes , Listeriosis , Ácidos Nucleicos , Antivirales/metabolismo , Citocinas/metabolismo , Células Dendríticas , Vesículas Extracelulares/metabolismo , Humanos , Inmunidad Innata , Ácidos Nucleicos/metabolismo
8.
Front Immunol ; 8: 1854, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29312336

RESUMEN

Tetraspanins are a family of proteins with four transmembrane domains that associate between themselves and cluster with other partner proteins, conforming a distinct class of membrane domains, the tetraspanin-enriched microdomains (TEMs). These TEMs constitute macromolecular signaling platforms that regulate key processes in several cellular settings controlling signaling thresholds and avidity of receptors. In this study, we investigated the role of CD9, a tetraspanin that regulates major biological processes such as cell migration and immunological responses, in two mouse models of colitis that have been used to study the pathogenesis of inflammatory bowel disease (IBD). Previous in vitro studies revealed an important role in the interaction of leukocytes with inflamed endothelium, but in vivo evidence of the involvement of CD9 in inflammatory diseases is scarce. Here, we studied the role of CD9 in the pathogenesis of colitis in vivo. Colitis was induced by administration of dextran sodium sulfate (DSS), a chemical colitogen that causes epithelial disruption and intestinal inflammation. CD9-/- mice showed less severe colitis than wild-type counterparts upon exposure to DSS (2% solution) and enhanced survival in response to a lethal DSS dose (4%). Decreased neutrophil and macrophage cell infiltration was observed in colonic tissue from CD9-/- animals, in accordance with their lower serum levels of TNF-α, IL-6, and other proinflammatory cytokines in the colon. The specific role of CD9 in IBD was further dissected by transfer of CD4+ CD45RBhi naive T cells into the Rag1-/- mouse colitis model. However, no significant differences were observed in these settings between both groups, ruling out a role for CD9 in IBD in the lymphoid compartment. Experiments with bone marrow chimeras revealed that CD9 in the non-hematopoietic compartment is involved in colon injury and limits the proliferation of epithelial cells. Our data indicate that CD9 in non-hematopoietic cells plays an important role in colitis by limiting epithelial cell proliferation. Future strategies to repress CD9 expression may be of therapeutic benefit in the treatment of IBD.

9.
Nat Commun ; 7: 13588, 2016 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-27882925

RESUMEN

Exosomes are vesicles secreted to the extracellular environment through fusion with the plasma membrane of specific endosomes called multivesicular bodies (MVB) and mediate cell-to-cell communication in many biological processes. Posttranslational modifications are involved in the sorting of specific proteins into exosomes. Here we identify ISGylation as a ubiquitin-like modification that controls exosome release. ISGylation induction decreases MVB numbers and impairs exosome secretion. Using ISG15-knockout mice and mice expressing the enzymatically inactive form of the de-ISGylase USP18, we demonstrate in vitro and in vivo that ISG15 conjugation regulates exosome secretion. ISG15 conjugation triggers MVB co-localization with lysosomes and promotes the aggregation and degradation of MVB proteins. Accordingly, inhibition of lysosomal function or autophagy restores exosome secretion. Specifically, ISGylation of the MVB protein TSG101 induces its aggregation and degradation, being sufficient to impair exosome secretion. These results identify ISGylation as a novel ubiquitin-like modifier in the control of exosome production.


Asunto(s)
Citocinas/genética , Proteínas de Unión al ADN/metabolismo , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , Exosomas/metabolismo , Lisosomas/metabolismo , Cuerpos Multivesiculares/metabolismo , Factores de Transcripción/metabolismo , Animales , Autofagia , Células HEK293 , Humanos , Células Jurkat , Macrófagos , Ratones , Ratones Noqueados , Linfocitos T , Ubiquitina Tiolesterasa/metabolismo , Ubiquitinas/genética
10.
Front Immunol ; 5: 383, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25157254

RESUMEN

Exosomes mediate intercellular communication and participate in many cell processes such as cancer progression, immune activation or evasion, and the spread of infection. Exosomes are small vesicles secreted to the extracellular environment through the release of intraluminal vesicles contained in multivesicular bodies (MVBs) upon the fusion of these MVBs with the plasma membrane. The composition of exosomes is not random, suggesting that the incorporation of cargo into them is a regulated process. However, the mechanisms that control the sorting of protein cargo into exosomes are currently elusive. Here, we review the post-translational modifications detected in exosomal proteins, and discuss their possible role in their specific sorting into exosomes.

11.
Mol Biol Cell ; 23(12): 2253-63, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22535526

RESUMEN

Syntenin-1 is a cytosolic adaptor protein involved in several cellular processes requiring polarization. Human immunodeficiency virus type 1 (HIV-1) attachment to target CD4(+) T-cells induces polarization of the viral receptor and coreceptor, CD4/CXCR4, and cellular structures toward the virus contact area, and triggers local actin polymerization and phosphatidylinositol 4,5-bisphosphate (PIP(2)) production, which are needed for successful HIV infection. We show that syntenin-1 is recruited to the plasma membrane during HIV-1 attachment and associates with CD4, the main HIV-1 receptor. Syntenin-1 overexpression inhibits HIV-1 production and HIV-mediated cell fusion, while syntenin depletion specifically increases HIV-1 entry. Down-regulation of syntenin-1 expression reduces F-actin polymerization in response to HIV-1. Moreover, HIV-induced PIP(2) accumulation is increased in syntenin-1-depleted cells. Once the virus has entered the target cell, syntenin-1 polarization toward the viral nucleocapsid is lost, suggesting a spatiotemporal regulatory role of syntenin-1 in actin remodeling, PIP(2) production, and the dynamics of HIV-1 entry.


Asunto(s)
VIH-1/fisiología , Sinteninas/metabolismo , Linfocitos T/virología , Internalización del Virus , Actinas/metabolismo , Antígenos CD4/metabolismo , Fusión Celular , Línea Celular , Línea Celular Tumoral , Membrana Celular/metabolismo , Células Gigantes , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , VIH-1/metabolismo , Interacciones Huésped-Patógeno , Humanos , Immunoblotting , Inmunoprecipitación , Células Jurkat , Microscopía Confocal , Mutación , Fosfatidilinositol 4,5-Difosfato/metabolismo , Unión Proteica , Interferencia de ARN , Sinteninas/genética , Linfocitos T/metabolismo
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