RESUMO
Humoral autoimmunity paralleled by the accumulation of follicular helper T cells (T(FH) cells) is linked to mutation of the gene encoding the RNA-binding protein roquin-1. Here we found that T cells lacking roquin caused pathology in the lung and accumulated as cells of the T(H)17 subset of helper T cells in the lungs. Roquin inhibited T(H)17 cell differentiation and acted together with the endoribonuclease regnase-1 to repress target mRNA encoding the T(H)17 cell-promoting factors IL-6, ICOS, c-Rel, IRF4, IκBNS and IκBζ. This cooperation required binding of RNA by roquin and the nuclease activity of regnase-1. Upon recognition of antigen by the T cell antigen receptor (TCR), roquin and regnase-1 proteins were cleaved by the paracaspase MALT1. Thus, this pathway acts as a 'rheostat' by translating TCR signal strength via graded inactivation of post-transcriptional repressors and differential derepression of targets to enhance T(H)17 differentiation.
Assuntos
Caspases/metabolismo , Proteínas de Neoplasias/metabolismo , Receptores de Antígenos de Linfócitos T/imunologia , Ribonucleases/metabolismo , Células Th17/citologia , Ubiquitina-Proteína Ligases/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Sequência de Aminoácidos , Animais , Sítios de Ligação/imunologia , Diferenciação Celular/imunologia , Linhagem Celular , Genes rel/genética , Células HEK293 , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Fatores Reguladores de Interferon/genética , Interleucina-6/genética , Peptídeos e Proteínas de Sinalização Intracelular , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa , Proteínas Nucleares/genética , Proteínas/genética , RNA Mensageiro/genética , Proteínas de Ligação a RNA/metabolismo , Alinhamento de Sequência , Células Th17/imunologia , Ubiquitina-Proteína Ligases/genéticaRESUMO
The Roquin-1 protein binds to messenger RNAs (mRNAs) and regulates gene expression posttranscriptionally. A single point mutation in Roquin-1, but not gene ablation, increases follicular helper T (Tfh) cell numbers and causes lupus-like autoimmune disease in mice. In T cells, we did not identify a unique role for the much lower expressed paralog Roquin-2. However, combined ablation of both genes induced accumulation of T cells with an effector and follicular helper phenotype. We showed that Roquin-1 and Roquin-2 proteins redundantly repressed the mRNA of inducible costimulator (Icos) and identified the Ox40 costimulatory receptor as another shared mRNA target. Combined acute deletion increased Ox40 signaling, as well as Irf4 expression, and imposed Tfh differentiation on CD4(+) T cells. These data imply that both proteins maintain tolerance by preventing inappropriate T cell activation and Tfh cell differentiation, and that Roquin-2 compensates in the absence of Roquin-1, but not in the presence of its mutated form.
Assuntos
Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , RNA Mensageiro/metabolismo , Receptores OX40/metabolismo , Proteínas Repressoras/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Antígenos CD4/metabolismo , Diferenciação Celular/genética , Células HEK293 , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/genética , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Mutantes , Ligação Proteica , Receptores OX40/genética , Proteínas Repressoras/genética , Ubiquitina-Proteína Ligases/genéticaRESUMO
Post-transcriptional gene regulation by RNA-binding proteins controls mRNA half-life and efficiency of translation. Recently, the RNA-binding proteins Roquin and Regnase-1 have been shown to play pivotal roles in T lymphocytes by preventing inflammatory and autoimmune disease. These factors share an overlapping set of target mRNAs and are both regulated by proteolytic cleavage through the paracaspase MALT1. This review discusses the mouse models of inactivation or deregulation and how these trans-acting factors recognize target mRNAs. Based on different affinities of cis-elements in target mRNAs and regulation of the trans-acting factors, we propose the following model: Increasing TCR signal strength will gradually inactivate Roquin and Regnase-1 causing differential target mRNA derepression that specifies cell fate decisions and effector functions of T cells.
Assuntos
Autoimunidade/imunologia , Proteínas de Ligação a RNA/fisiologia , Transdução de Sinais/fisiologia , Linfócitos T/imunologia , Animais , Diferenciação Celular , HumanosRESUMO
The paracaspase Malt1 is a central regulator of antigen receptor signaling that is frequently mutated in human lymphoma. As a scaffold, it assembles protein complexes for NF-κB activation, and its proteolytic domain cleaves negative NF-κB regulators for signal enforcement. Still, the physiological functions of Malt1-protease are unknown. We demonstrate that targeted Malt1-paracaspase inactivation induces a lethal inflammatory syndrome with lymphocyte-dependent neurodegeneration in vivo. Paracaspase activity is essential for regulatory T cell (Treg) and innate-like B cell development, but it is largely dispensable for overcoming Malt1-dependent thresholds for lymphocyte activation. In addition to NF-κB inhibitors, Malt1 cleaves an entire set of mRNA stability regulators, including Roquin-1, Roquin-2, and Regnase-1, and paracaspase inactivation results in excessive interferon gamma (IFNγ) production by effector lymphocytes that drive pathology. Together, our results reveal distinct threshold and modulatory functions of Malt1 that differentially control lymphocyte differentiation and activation pathways and demonstrate that selective paracaspase blockage skews systemic immunity toward destructive autoinflammation.