RESUMO
Deficiency in mevalonate kinase (MVK) causes systemic inflammation. However, the molecular mechanisms linking the mevalonate pathway to inflammation remain obscure. Geranylgeranyl pyrophosphate, a non-sterol intermediate of the mevalonate pathway, is the substrate for protein geranylgeranylation, a protein post-translational modification that is catalyzed by protein geranylgeranyl transferase I (GGTase I). Pyrin is an innate immune sensor that forms an active inflammasome in response to bacterial toxins. Mutations in MEFV (encoding human PYRIN) result in autoinflammatory familial Mediterranean fever syndrome. We found that protein geranylgeranylation enabled Toll-like receptor (TLR)-induced activation of phosphatidylinositol-3-OH kinase (PI(3)K) by promoting the interaction between the small GTPase Kras and the PI(3)K catalytic subunit p110δ. Macrophages that were deficient in GGTase I or p110δ exhibited constitutive release of interleukin 1ß that was dependent on MEFV but independent of the NLRP3, AIM2 and NLRC4 inflammasomes. In the absence of protein geranylgeranylation, compromised PI(3)K activity allows an unchecked TLR-induced inflammatory responses and constitutive activation of the Pyrin inflammasome.
Assuntos
Alquil e Aril Transferases/metabolismo , Febre Familiar do Mediterrâneo/metabolismo , Inflamassomos/metabolismo , Macrófagos/fisiologia , Mutação/genética , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Pirina/genética , Alquil e Aril Transferases/genética , Animais , Células Cultivadas , Febre Familiar do Mediterrâneo/genética , Humanos , Imunidade Inata , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Fosfatos de Poli-Isoprenil/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Receptores Toll-Like/metabolismoRESUMO
Anaplastic large cell lymphoma (ALCL) is a T-cell malignancy predominantly driven by a hyperactive anaplastic lymphoma kinase (ALK) fusion protein. ALK inhibitors, such as crizotinib, provide alternatives to standard chemotherapy with reduced toxicity and side effects. Children with lymphomas driven by nucleophosmin 1 (NPM1)-ALK fusion proteins achieved an objective response rate to ALK inhibition therapy of 54% to 90% in clinical trials; however, a subset of patients progressed within the first 3 months of treatment. The mechanism for the development of ALK inhibitor resistance is unknown. Through genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) activation and knockout screens in ALCL cell lines, combined with RNA sequencing data derived from ALK inhibitor-relapsed patient tumors, we show that resistance to ALK inhibition by crizotinib in ALCL can be driven by aberrant upregulation of interleukin 10 receptor subunit alpha (IL10RA). Elevated IL10RA expression rewires the STAT3 signaling pathway, bypassing otherwise critical phosphorylation by NPM1-ALK. IL-10RA expression does not correlate with response to standard chemotherapy in pediatric patients, suggesting that a combination of crizotinib and chemotherapy could prevent ALK inhibitor resistance-specific relapse.
Assuntos
Antineoplásicos/farmacologia , Crizotinibe/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Subunidade alfa de Receptor de Interleucina-10/genética , Linfoma Anaplásico de Células Grandes/genética , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/genética , Antineoplásicos/uso terapêutico , Sistemas CRISPR-Cas , Linhagem Celular , Crizotinibe/uso terapêutico , Relação Dose-Resposta a Droga , Edição de Genes , Expressão Gênica , Humanos , Imuno-Histoquímica , Subunidade alfa de Receptor de Interleucina-10/metabolismo , Linfoma Anaplásico de Células Grandes/tratamento farmacológico , Linfoma Anaplásico de Células Grandes/metabolismo , Linfoma Anaplásico de Células Grandes/patologia , Modelos Biológicos , Nucleofosmina , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Multiple clinical trials have shown that the 3-hydroxyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins have anti-inflammatory effects. However, the underlying molecular mechanism remains unclear. The proinflammatory cytokine interleukin-1ß (IL-1ß) is synthesized as a non-active precursor. The 31-kDa pro-IL-1ß is processed into the 17-kDa active form by caspase-1-activating inflammasomes. Here, we report a novel signaling pathway induced by statins, which leads to processing of pro-IL-1ß into an intermediate 28-kDa form. This statin-induced IL-1ß processing is independent of caspase-1- activating inflammasomes. The 28-kDa form of IL-1ß cannot activate interleukin-1 receptor-1 (IL1R1) to signal inflammatory responses. Instead, it interferes with mature IL-1ß signaling through IL-1R1 and therefore may dampen inflammatory responses initiated by mature IL-1ß. These results may provide new clues to explain the anti-inflammatory effects of statins.