| First Author | Bresque M | Year | 2022 |
| Journal | J Biol Chem | Volume | 298 |
| Issue | 3 | Pages | 101711 |
| PubMed ID | 35150745 | Mgi Jnum | J:330260 |
| Mgi Id | MGI:7257371 | Doi | 10.1016/j.jbc.2022.101711 |
| Citation | Bresque M, et al. (2022) SIRT6 stabilization and cytoplasmic localization in macrophages regulates acute and chronic inflammation in mice. J Biol Chem :101711 |
| abstractText | Acute and chronic inflammation are key homeostatic events in health and disease. Sirtuins, a family of NAD-dependent protein deacylases, play a pivotal role in the regulation of these inflammatory responses. Indeed, sirtuins have anti-inflammatory effects through a myriad of signalling cascades, including histone deacetylation and gene silencing, p65/RelA deacetylation and inactivation, and NLRP3 inflammasome inhibition. Nevertheless, recent findings show that sirtuins, specifically SIRT6, are also necessary for mounting an active inflammatory response in macrophages. SIRT6 has been shown to positively regulate tumor necrosis factor (TNF)-a secretion by demiristoylating pro-TNFa in the cytoplasm. However, how SIRT6, a nuclear, chromatin binding protein, fulfills this function in the cytoplasm is currently unknown. Herein, we show by western blot and immunofluorescence, that in macrophages and fibroblasts there is a sub-population of SIRT6 that is highly unstable and is quickly degraded via the proteasome. Upon LPS stimulation in Raw 264.7, bone marrow and peritoneal macrophages, this population of SIRT6 is rapidly stabilized and localizes in the cytoplasm, specifically in the vicinity of the endoplasmic reticulum (ER), promoting TNFa secretion. Further, we also found that acute SIRT6 inhibition dampens TNFa secretion both in vitro and in vivo, decreasing LPS-induced septic shock. Finally, we tested SIRT6 relevance in systemic inflammation using an obesity-induced chronic inflammatory in vivo model, where TNFa plays a key role, and we show that short term genetic deletion of SIRT6 in macrophages of obese mice ameliorated systemic inflammation and hyperglycemia, suggesting that SIRT6 plays and active role in inflammation-mediated glucose intolerance during obesity. |
