| First Author | Zhou N | Year | 2022 |
| Journal | Cell Metab | Volume | 34 |
| Issue | 7 | Pages | 1023-1041.e8 |
| PubMed ID | 35675826 | Mgi Jnum | J:351461 |
| Mgi Id | MGI:7311472 | Doi | 10.1016/j.cmet.2022.05.005 |
| Citation | Zhou N, et al. (2022) Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses. Cell Metab 34(7):1023-1041.e8 |
| abstractText | The ovarian-tumor-domain-containing deubiquitinases (OTUDs) block ubiquitin-dependent protein degradation and are involved in diverse signaling pathways. We discovered a rare OTUD3 c.863G>A mutation in a family with an early age of onset of diabetes. This mutation reduces the stability and catalytic activity of OTUD3. We next constructed an experiment with Otud3(-/-) mice and found that they developed worse obesity, dyslipidemia, and insulin resistance than wild-type mice when challenged with a high-fat diet (HFD). We further found that glucose and fatty acids stimulate CREB-binding-protein-dependent OTUD3 acetylation, promoting its nuclear translocation, where OTUD3 regulates various genes involved in glucose and lipid metabolism and oxidative phosphorylation by stabilizing peroxisome-proliferator-activated receptor delta (PPARdelta). Moreover, targeting PPARdelta using a specific agonist can partially rescue the phenotype of HFD-fed Otud3(-/-) mice. We propose that OTUD3 is an important regulator of energy metabolism and that the OTUD3 c.863G>A is associated with obesity and a higher risk of diabetes. |
