RESUMO
Rheumatoid arthritis (RA) and ankylosing spondylitis (AS) are chronic inflammatory diseases that together affect 2-3% of the population. RA and AS predominantly involve joints, but heart disease is also a common feature in RA and AS patients. Here we have studied a new spontaneous mutation that causes severe polyarthritis in bone phenotype spontaneous mutation 1 (BPSM1) mice. In addition to joint destruction, mutant mice also develop aortic root aneurism and aorto-mitral valve disease that can be fatal depending on the genetic background. The cause of the disease is the spontaneous insertion of a retrotransposon into the 3' untranslated region (3'UTR) of the tumor necrosis factor (TNF), which triggers its strong overexpression in myeloid cells. We found that several members of a family of RNA-binding, CCCH-containing zinc-finger proteins control TNF expression through its 3'UTR, and we identified a previously unidentified regulatory element in the UTR. The disease in BPSM1 mice is independent of the adaptive immune system and does not appear to involve inflammatory cytokines other than TNF. To our knowledge, this is the first animal model showing both polyarthritis and heart disease as a direct result of TNF deregulation. These results emphasize the therapeutic potential of anti-TNF drugs for the treatment of heart valve disease and identify potential therapeutic targets to control TNF expression and inflammation.
Assuntos
Regiões 3' não Traduzidas/genética , Artrite/genética , Doenças das Valvas Cardíacas/genética , Mutagênese Insercional/genética , Mutação/genética , Retroelementos/genética , Fator de Necrose Tumoral alfa/genética , Aneurisma/patologia , Animais , Insuficiência da Valva Aórtica/complicações , Insuficiência da Valva Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/patologia , Artrite/sangue , Artrite/diagnóstico por imagem , Artrite/patologia , Sequência de Bases , Transplante de Medula Óssea , Quimiocinas/sangue , Doença Crônica , Modelos Animais de Doenças , Fibrose , Doenças das Valvas Cardíacas/sangue , Doenças das Valvas Cardíacas/diagnóstico por imagem , Doenças das Valvas Cardíacas/patologia , Humanos , Inflamação/patologia , Articulações/patologia , Camundongos Mutantes , Valva Mitral/patologia , Dados de Sequência Molecular , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Elementos Nucleotídeos Curtos e Dispersos/genética , Fator de Necrose Tumoral alfa/metabolismo , Ultrassonografia , Microtomografia por Raio-X , Dedos de Zinco/genéticaRESUMO
CCCH zinc finger proteins (ZFPs) function mainly as RNA-binding proteins (RBPs) and play a central role in the mRNA metabolism. Over twenty seven CCCH-ZFPs are encoded in the genome of the human malaria parasite Plasmodium falciparum, the causative agent of malaria tropica. However, little is known about their functions. In this study, we characterize one member of the PfCCCH-ZFP named ZNF4. We show that ZNF4 is highly expressed in mature gametocytes, where it predominantly localizes to the cytoplasm. Targeted gene disruption of ZNF4 showed no significant effect in asexual blood stage replication and gametocyte development while male gametocyte exflagellation was significantly impaired, leading to reduced malaria transmission in the mosquito. Comparative transcriptomics between wildtype (WT) and the ZNF4-deficient line (ZNF4-KO) demonstrated the deregulation of about 473 genes (274 upregulated and 199 downregulated) in mature gametocytes. Most of the downregulated genes show peak expression in mature gametocyte with male enriched genes associated to the axonemal dynein complex formation, and cell projection organization is highly affected, pointing to the phenotype in male gametocyte exflagellation. Upregulated genes are associated to ATP synthesis. Our combined data therefore indicate that ZNF4 is a CCCH zinc finger protein which plays an important role in male gametocyte exflagellation through the regulation of male gametocyte-enriched genes.