detail content area
Experimental & Molecilar Medicine, 2019. 51(9), 107-, DOI: https://doi.org/10.1038/s12276-019-0309-0
Deacetylation of XBP1s by sirtuin 6 confers resistance to ER stress-induced hepatic steatosis
In Hyuk Bang, Oh Kwang Kwon;Lihua Hao;Dami Park;Myung-Ja Chung;Byung-Chul Oh;Sangkyu Lee;Eun Ju Bae;Byung-Hyun Park;Eun Ju Bae and Byung-Hyun Park
The active spliced form of X-box-binding protein 1 (XBP1s) is a key modulator of ER stress, but the functional role of its post-translational modification remains unclear. Here, we demonstrate that XBP1s is a deacetylation target of Sirt6 and that its deacetylation protects against ER stress-induced hepatic steatosis. Specifically, the abundance of acetylated XBP1s and concordant hepatic steatosis were increased in hepatocyte-specific Sirt6 knockout and obese mice but were decreased by genetic overexpression and pharmacological activation of Sirt6. Mechanistically, we identified that Sirt6 deacetylated a transactivation domain of XBP1s at Lys257 and Lys297 and promoted XBP1s protein degradation through the ubiquitin-proteasome system. Overexpression of XBP1s, but not its deacetylation mutant 2KR (K257/297R), in mice increased lipid accumulation in the liver. Importantly, in liver tissues obtained from patients with nonalcoholic fatty liver disease (NAFLD), the extent of XBP1s acetylation correlated positively with the NAFLD activity score but negatively with the Sirt6 level. Collectively, we present direct evidence supporting the importance of XBP1 acetylation in ER stress-induced hepatic steatosis.
- DOI: https://doi.org/10.1038/s12276-019-0309-0
- ISBN or ISSN: 1226-3613
- 본 연구는 질병관리본부 연구개발과제연구비를 지원받아 수행되었습니다.
- This research was supported by a fund by Research of Korea Centers for Disease Control and Prevention.