RESUMEN
Interleukin 1 beta (IL-1 beta) is a potent proinflammatory factor during viral infection. Its production is tightly controlled by transcription of Il1b dependent on the transcription factor NF-kappaB and subsequent processing of pro-IL-1 beta by an inflammasome. However, the sensors and mechanisms that facilitate RNA virus-induced production of IL-1 beta are not well defined. Here we report a dual role for the RNA helicase RIG-I in RNA virus-induced proinflammatory responses. Whereas RIG-I-mediated activation of NF-kappaB required the signaling adaptor MAVS and a complex of the adaptors CARD9 and Bcl-10, RIG-I also bound to the adaptor ASC to trigger caspase-1-dependent inflammasome activation by a mechanism independent of MAVS, CARD9 and the Nod-like receptor protein NLRP3. Our results identify the CARD9-Bcl-10 module as an essential component of the RIG-I-dependent proinflammatory response and establish RIG-I as a sensor able to activate the inflammasome in response to certain RNA viruses.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , ARN Helicasas DEAD-box/metabolismo , Inflamación/fisiopatología , Interleucina-1beta/metabolismo , Virus ARN/fisiología , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Proteínas Adaptadoras de Señalización CARD , Caspasa 1/metabolismo , Línea Celular , Células Cultivadas , Proteína 58 DEAD Box , ARN Helicasas DEAD-box/genética , Virus de la Encefalomiocarditis/inmunología , Virus de la Encefalomiocarditis/fisiología , Activación Enzimática , Ensayo de Inmunoadsorción Enzimática , Interacciones Huésped-Patógeno , Humanos , Immunoblotting , Inflamación/inmunología , Inflamación/virología , Helicasa Inducida por Interferón IFIH1 , Ratones , Ratones Noqueados , Modelos Biológicos , Infecciones por Virus ARN/inmunología , Infecciones por Virus ARN/fisiopatología , Infecciones por Virus ARN/virología , Virus ARN/inmunología , Virus de la Estomatitis Vesicular Indiana/inmunología , Virus de la Estomatitis Vesicular Indiana/fisiología , Proteína bcl-X/genética , Proteína bcl-X/metabolismoRESUMEN
Fungal infections are increasing worldwide due to the marked rise in immunodeficiencies including AIDS; however, immune responses to fungi are poorly understood. Dectin-1 is the major mammalian pattern recognition receptor for the fungal component zymosan. Dectin-1 represents the prototype of innate non-Toll-like receptors (TLRs) containing immunoreceptor tyrosine-based activation motifs (ITAMs) related to those of adaptive antigen receptors. Here we identify Card9 as a key transducer of Dectin-1 signalling. Although being dispensable for TLR/MyD88-induced responses, Card9 controls Dectin-1-mediated myeloid cell activation, cytokine production and innate anti-fungal immunity. Card9 couples to Bcl10 and regulates Bcl10-Malt1-mediated NF-kappaB activation induced by zymosan. Yet, Card9 is dispensable for antigen receptor signalling that uses Carma1 as a link to Bcl10-Malt1. Thus, our results define a novel innate immune pathway and indicate that evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10-Malt1 module.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Hongos/inmunología , Inmunidad Innata/inmunología , Transducción de Señal , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Antígenos Fúngicos/inmunología , Proteína 10 de la LLC-Linfoma de Células B , Proteínas Adaptadoras de Señalización CARD , Candida albicans/inmunología , Caspasas/metabolismo , Citocinas/biosíntesis , Citocinas/inmunología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lectinas Tipo C , Activación de Linfocitos/inmunología , Proteínas de la Membrana/metabolismo , Ratones , Proteína 1 de la Translocación del Linfoma del Tejido Linfático Asociado a Mucosas , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Quinasa Syk , Receptores Toll-Like , Zimosan/inmunologíaRESUMEN
Novel vaccination strategies against Mycobacterium tuberculosis (MTB) are urgently needed. The use of recombinant MTB antigens as subunit vaccines is a promising approach, but requires adjuvants that activate antigen-presenting cells (APCs) for elicitation of protective immunity. The mycobacterial cord factor Trehalose-6,6-dimycolate (TDM) and its synthetic analogue Trehalose-6,6-dibehenate (TDB) are effective adjuvants in combination with MTB subunit vaccine candidates in mice. However, it is unknown which signaling pathways they engage in APCs and how these pathways are coupled to the adaptive immune response. Here, we demonstrate that these glycolipids activate macrophages and dendritic cells (DCs) via Syk-Card9-Bcl10-Malt1 signaling to induce a specific innate activation program distinct from the response to Toll-like receptor (TLR) ligands. APC activation by TDB and TDM was independent of the C-type lectin receptor Dectin-1, but required the immunoreceptor tyrosine-based activation motif-bearing adaptor protein Fc receptor gamma chain (FcRgamma). In vivo, TDB and TDM adjuvant activity induced robust combined T helper (Th)-1 and Th-17 T cell responses to a MTB subunit vaccine and partial protection against MTB challenge in a Card9-dependent manner. These data provide a molecular basis for the immunostimulatory activity of TDB and TDM and identify the Syk-Card9 pathway as a rational target for vaccine development against tuberculosis.