TP53INP2 regulates adiposity by activating β-catenin through autophagy-dependent sequestration of GSK3β
| Autor: | Víctor A. Francis, M. Romero, Ann Hammarstedt, Joan Vendrell, José Manuel Fernández-Real, Ignacio Castrillon-Rodríguez, Xavier Duran, Ulf Smith, Manuela Sánchez-Feutrie, Antonio Zorzano, José María Moreno-Navarrete, Angels Díaz-Ramos, Manuel Palacín, Birgit Gustafson, Alba Sabaté-Pérez |
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| Rok vydání: | 2018 |
| Předmět: |
Adult
Male Transcriptional Activation 0301 basic medicine Cell signaling Time Factors Endosome 030209 endocrinology & metabolism Endosomes ESCRT Mice 03 medical and health sciences 0302 clinical medicine 3T3-L1 Cells Adipocytes Autophagy Animals Humans Wnt Signaling Pathway beta Catenin Adiposity Mice Knockout Sweden Adipogenesis Glycogen Synthase Kinase 3 beta Hyperplasia Endosomal Sorting Complexes Required for Transport Activator (genetics) Chemistry Wnt signaling pathway Nuclear Proteins Cell Biology Middle Aged Cell biology Mice Inbred C57BL Protein Transport 030104 developmental biology Adipose Tissue Spain Catenin Female TCF Transcription Factors |
| Zdroj: | Nature Cell Biology. 20:443-454 |
| ISSN: | 1476-4679 1465-7392 |
| DOI: | 10.1038/s41556-018-0072-9 |
| Popis: | Excessive fat accumulation is a major risk factor for the development of type 2 diabetes mellitus and other common conditions, including cardiovascular disease and certain types of cancer. Here, we identify a mechanism that regulates adiposity based on the activator of autophagy TP53INP2. We report that TP53INP2 is a negative regulator of adipogenesis in human and mouse preadipocytes. In keeping with this, TP53INP2 ablation in mice caused enhanced adiposity, which was characterized by greater cellularity of subcutaneous adipose tissue and increased expression of master adipogenic genes. TP53INP2 modulates adipogenesis through autophagy-dependent sequestration of GSK3β into late endosomes. GSK3β sequestration was also dependent on ESCRT activity. As a result, TP53INP2 promotes greater β-catenin levels and induces the transcriptional activity of TCF/LEF transcription factors. These results demonstrate a link between autophagy, sequestration of GSK3β into late endosomes and inhibition of adipogenesis in vivo. |
| Databáze: | OpenAIRE |
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