Ubiquitination Regulates the Proteasomal Degradation and Nuclear Translocation of the Fat Mass and Obesity-Associated (FTO) Protein
| Autor: | Victor Anggono, Di Xia, Tianyi Zhu, Jocelyn Widagdo, Xuan Ling Hilary Yong |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Proteasome Endopeptidase Complex endocrine system diseases Active Transport Cell Nucleus Alpha-Ketoglutarate-Dependent Dioxygenase FTO medicine.disease_cause Ribosomal s6 kinase 03 medical and health sciences Ubiquitin Structural Biology medicine Humans Phosphorylation Molecular Biology Mutation biology Chemistry Ribosomal Protein S6 Kinases Ubiquitination Protein turnover nutritional and metabolic diseases pathological conditions signs and symptoms Subcellular localization Cell biology 030104 developmental biology Proteostasis Proteasome Proteolysis biology.protein HeLa Cells |
| Zdroj: | Journal of Molecular Biology. 430:363-371 |
| ISSN: | 0022-2836 |
| DOI: | 10.1016/j.jmb.2017.12.003 |
| Popis: | Genetic polymorphisms in the fat mass and obesity-associated (FTO) gene have been strongly associated with obesity in humans. The cellular level of FTO is tightly regulated, with alterations in its expression influencing energy metabolism, food intake and body weight. Although the proteasome system is involved, the cellular mechanism underlying FTO protein turnover remains unknown. Here, we report that FTO undergoes post-translational ubiquitination on Lys-216. Knock-in HeLa cells harboring the ubiquitin-deficient K216R mutation displayed a slower rate of FTO turnover, resulting in an increase in the level of FTO as well as enhanced phosphorylation of the ribosomal S6 kinase. Surprisingly, we also found that K216R mutation reduced the level of nuclear FTO and completely abolished the nuclear translocation of FTO in response to amino acid starvation. Collectively, our results reveal the functional importance of ubiquitination in controlling FTO expression and localization, which may be crucial for determining body mass and composition. |
| Databáze: | OpenAIRE |
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