RESUMEN
Innate immunity conferred by the type I interferon is critical for antiviral defense. To date only a limited number of tripartite motif (TRIM) proteins have been implicated in modulation of innate immunity and anti-microbial activity. Here we report the complementary DNA cloning and systematic analysis of all known 75 human TRIMs. We demonstrate that roughly half of the 75 TRIM-family members enhanced the innate immune response and that they do this at multiple levels in signaling pathways. Moreover, messenger RNA levels and localization of most of these TRIMs were found to be altered during viral infection, suggesting that their regulatory activities are highly controlled at both pre- and posttranscriptional levels. Taken together, our data demonstrate a very considerable dedication of this large protein family to the positive regulation of the antiviral response, which supports the notion that this family of proteins evolved as a component of innate immunity.
Asunto(s)
Proteínas Portadoras/genética , Inmunidad Innata , Leucocitos Mononucleares/metabolismo , ARN Mensajero/genética , Receptores de Reconocimiento de Patrones/genética , Infecciones por Rhabdoviridae/metabolismo , Dedos de Zinc/genética , Empalme Alternativo , Factores de Restricción Antivirales , Proteínas Portadoras/antagonistas & inhibidores , Proteínas Portadoras/inmunología , Línea Celular , Clonación Molecular , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Humanos , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/virología , Isoformas de Proteínas/antagonistas & inhibidores , Isoformas de Proteínas/genética , Isoformas de Proteínas/inmunología , ARN Mensajero/inmunología , ARN Interferente Pequeño/genética , Receptores de Reconocimiento de Patrones/inmunología , Infecciones por Rhabdoviridae/inmunología , Infecciones por Rhabdoviridae/virología , Transducción de Señal , Proteínas de Motivos Tripartitos , Ubiquitina-Proteína Ligasas , Vesiculovirus/inmunología , Dedos de Zinc/inmunologíaRESUMEN
The tripartite motif (TRIM) proteins are important in a variety of cellular functions additional to anti-viral activity. We systematically analysed mRNA expression of representative TRIM molecules in mouse macrophages, myeloid and plasmacytoid dendritic cells, and a selection of CD4(+) T cell subsets. We defined four clusters of TRIM genes based on their selective expression in these cells. The first group of TRIM genes was preferentially expressed in CD4(+) T cells and contained the COS-FN3 motif previously shown to be involved in protein interactions. Additional TRIM genes were identified that showed up-regulation in macrophages and dendritic cells upon influenza virus infection in a type I IFN-dependent manner, suggesting that they have anti-viral activity. In support of this notion, a subset of these TRIM molecules mapped to mouse chromosome 7, syntenic to human chromosome 11, where TRIM family members such as TRIM5, shown to have anti-viral activity, are localized. A distinct group of TRIM was constitutively expressed in plasmacytoid dendritic cells independently of viral infection or signalling through the type I IFN receptor. Our findings on expression and regulation of TRIM genes in cells of the immune system that have different effector functions in innate and adaptive immune responses, may provide leads for determining functions of this diverse family of molecules.