Identification of TMEM131L as a novel regulator of thymocyte proliferation in humans
| Autor: | Aude Parcelier, Niclas Setterblad, Jean Claude Gluckman, Simona Denti, Elisabeth Nelson, Veronique Parietti, Bruno Canque, Marika Pla, Nesrine Maharzi, François Sigaux, Macarena Robledo-Sarmiento |
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| Rok vydání: | 2013 |
| Předmět: |
Thymocytes
Reverse Transcriptase Polymerase Chain Reaction Immunology Wnt signaling pathway Regulator LRP6 Membrane Proteins LRP5 Mice SCID Biology Cytoplasmic part Flow Cytometry Transmembrane protein Cell biology Thymocyte Mice HEK293 Cells Microscopy Fluorescence Mice Inbred NOD Immunology and Allergy Phosphorylation Animals Humans Wnt Signaling Pathway Cell Proliferation |
| Zdroj: | Journal of immunology (Baltimore, Md. : 1950). 190(12) |
| ISSN: | 1550-6606 |
| Popis: | In this study, we identify transmembrane protein 131–like (TMEM131L) as a novel regulator of thymocyte proliferation and demonstrate that it corresponds to a not as yet reported inhibitor of Wnt signaling. Short hairpin RNA–mediated silencing of TMEM131L in human CD34+ hematopoietic progenitors, which were then grafted in NOD-SCID/IL-2rγnull mice, resulted in both thymocyte hyperproliferation and multiple pre– and post–β-selection intrathymic developmental defects. Consistent with deregulated Wnt signaling, TMEM131L-deficient thymocytes expressed Wnt target genes at abnormally high levels, and they displayed both constitutive phosphorylation of Wnt coreceptor LRP6 and β-catenin intranuclear accumulation. Using T cell factor reporter assays, we found that membrane-associated TMEM131L inhibited canonical Wnt/β-catenin signaling at the LRP6 coreceptor level. Whereas membrane-associated TMEM131L did not affect LRP6 expression under basal conditions, it triggered lysosome-dependent degradation of its active phosphorylated form following Wnt activation. Genetic mapping showed that phosphorylated LRP6 degradation did not depend on TMEM131L cytoplasmic part but rather on a conserved extracellular domain proximal to the membrane. Collectively, these data indicate that, during thymopoiesis, stage-specific surface translocation of TMEM131L may regulate immature single-positive thymocyte proliferation arrest by acting through mixed Wnt-dependent and -independent mechanisms. |
| Databáze: | OpenAIRE |
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