RESUMO
Sensors that detect dsRNA stimulate IFN responses as a defense against viral infection. IFN responses are also well documented in a variety of human autoimmune diseases, including relapsing-remitting multiple sclerosis (MS), in which increased IFN responses result from increased levels of double-stranded endogenous Alu RNAs. Mechanisms underlying increases in double-stranded Alu RNAs in MS are obscure. We find widespread loss of adenosine-to-inosine editing of Alu RNAs in MS. Unedited Alu RNAs are potent activators of both IFN and NF-κB responses via the dsRNA sensors, RIG-I, and TLR3. Minor editing of highly active Alu elements abrogates the ability to activate both transcriptional responses. Thus, adenosine-to-inosine editing may also represent an important defense against autoimmune diseases such as MS.
Assuntos
Elementos Alu/imunologia , Esclerose Múltipla Recidivante-Remitente/genética , Edição de RNA/imunologia , RNA de Cadeia Dupla/imunologia , Ativação Transcricional/imunologia , Adenosina/genética , Elementos Alu/genética , Proteína DEAD-box 58/metabolismo , Conjuntos de Dados como Assunto , Células HEK293 , Humanos , Inflamação/genética , Inflamação/imunologia , Inosina/genética , Interferons/metabolismo , Esclerose Múltipla Recidivante-Remitente/sangue , Esclerose Múltipla Recidivante-Remitente/imunologia , NF-kappa B/metabolismo , RNA de Cadeia Dupla/genética , RNA de Cadeia Dupla/metabolismo , RNA-Seq , Receptores Imunológicos/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células THP-1 , Receptor 3 Toll-Like/metabolismo , Sequenciamento Completo do GenomaRESUMO
As a class, 'BET' inhibitors disrupt binding of bromodomain and extra-terminal motif (BET) proteins, BRD2, BRD3, BRD4 and BRDT, to acetylated histones preventing recruitment of RNA polymerase 2 to enhancers and promoters, especially super-enhancers, to inhibit gene transcription. As such, BET inhibitors may be useful therapeutics for treatment of cancer and inflammatory disease. For example, the small molecule BET inhibitor, JQ1, selectively represses MYC, an important oncogene regulated by a super-enhancer. IFN-γ, a critical cytokine for both innate and adaptive immune responses, is also regulated by a super-enhancer. Here, we show that JQ1 represses IFN-γ expression in TH1 polarized PBMC cultures, CD4+ memory T cells, and NK cells. JQ1 treatment does not reduce activating chromatin marks at the IFNG locus, but displaces RNA polymerase II from the locus. Further, IFN-γ expression recovers in polarized TH1 cultures following removal of JQ1. Our results show that JQ1 abrogates IFN-γ expression, but repression is reversible. Thus, BET inhibitors may disrupt the normal functions of the innate and adaptive immune response.