RESUMEN
The melastatin-like transient-receptor-potential-7 protein (TRPM7), harbouring a cation channel and a serine/threonine kinase, has been implicated in thymopoiesis and cytokine expression. Here we show, by analysing TRPM7 kinase-dead mutant (Trpm7 R/R ) mice, that the enzymatic activity of the receptor is not essential for thymopoiesis, but is required for CD103 transcription and gut-homing of intra-epithelial lymphocytes. Defective T cell gut colonization reduces MHCII expression in intestinal epithelial cells. Mechanistically, TRPM7 kinase activity controls TGF-ß-induced CD103 expression and pro-inflammatory T helper 17, but not regulatory T, cell differentiation by modulating SMAD2. Notably, we find that the TRPM7 kinase activity promotes gut colonization by alloreactive T cells in acute graft-versus-host disease. Thus, our results unravel a function of TRPM7 kinase in T cell activity and suggest a therapeutic potential of kinase inhibitors in averting acute graft-versus-host disease.
Asunto(s)
Enfermedad Injerto contra Huésped/genética , Intestinos/inmunología , Linfopoyesis/genética , Linfocitos T Reguladores/citología , Canales Catiónicos TRPM/genética , Células Th17/citología , Animales , Antígenos CD/inmunología , Diferenciación Celular/genética , Genes MHC Clase II/genética , Genes MHC Clase II/inmunología , Enfermedad Injerto contra Huésped/inmunología , Cadenas alfa de Integrinas/inmunología , Ratones , Mutación , Proteína Smad2/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Canales Catiónicos TRPM/inmunología , Células Th17/inmunología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
In the recent years, the role of actin and actin-binding proteins in gene transcription has received considerable attention. Nuclear monomeric and polymerized actin and several actin binding proteins have been detected in the mammalian cell nucleus, although their roles in transcription are just beginning to emerge. Our group recently reported that the actin-binding protein Filamin A interacts with the transcriptional coactivator MKL1 to link actin polymerization with transcriptional activity of Serum Response Factor. Here we summarize the regulation and function of MKL1, and highlight this novel mechanism of MKL1 regulation through binding to Filamin A and its implications for cell migration.
Asunto(s)
Actinas/química , Multimerización de Proteína , Transcripción Genética , Animales , Movimiento Celular , Humanos , Estructura Cuaternaria de Proteína , Transactivadores/metabolismoRESUMEN
Megakaryoblastic leukemia 1 (MKL1) is a coactivator of serum response factor (SRF) that promotes the expression of genes associated with cell proliferation, motility, adhesion, and differentiation-processes that also involve dynamic cytoskeletal changes in the cell. MKL1 is inactive when bound to monomeric globular actin (G-actin), but signals that activate the small guanosine triphosphatase RhoA cause actin polymerization and MKL1 dissociation from G-actin. We found a new mechanism of MKL1 activation that is mediated through its binding to filamin A (FLNA), a protein that binds filamentous actin (F-actin). The interaction of FLNA and MKL1 was required for the expression of MKL1 target genes in primary fibroblasts, melanoma, mammary and hepatocellular carcinoma cells. We identified the regions of interaction between MKL1 and FLNA, and cells expressing an MKL1 mutant that was unable to bind FLNA exhibited impaired cell migration and reduced expression of MKL1-SRF target genes. Induction and repression of MKL1-SRF target genes correlated with increased or decreased MKL1-FLNA interaction, respectively. Lysophosphatidic acid-induced RhoA activation in primary human fibroblasts promoted the association of endogenous MKL1 with FLNA, whereas exposure to an actin polymerization inhibitor dissociated MKL1 from FLNA and decreased MKL1-SRF target gene expression in melanoma cells. Thus, FLNA functions as a positive cellular transducer linking actin polymerization to MKL1-SRF activity, counteracting the known repressive complex of MKL1 and monomeric G-actin.