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Inhibition of XBP1s ubiquitination enhances its protein stability and improves glucose homeostasis.
Metabolism ( IF 10.8 ) Pub Date : 2019-12-16 , DOI: 10.1016/j.metabol.2019.154046
Honglin Sun 1 , Gang Wei 1 , He Liu 1 , Danrui Xiao 2 , Jianbo Huang 1 , Junxi Lu 1 , Ji Miao 3 , Junli Liu 1 , Suzhen Chen 1
Affiliation  

BACKGROUND Hepatic ER stress is a risk factor of insulin resistance and type 2 diabetes. X-box binding protein 1 spliced (XBP1s), a transcription factor, plays a key role in ameliorating insulin resistance and maintaining glucose homeostasis. Unfortunately, the short half-life of the protein dampens its clinical application, and the specific site of lysine residue that could be ubiquitinated and involved in the degradation of XBP1s remains elusive. METHODS AND RESULTS Here, we identified K60 and K77 on XBP1s as two pivotal ubiquitin sites required for its proteasome-dependent degradation. We also constructed a double mutant form of XBP1s (K60/77R) and found that it showed higher capacity in resisting against ubiquitin-mediated protein degradation, increasing nuclear translocation, enhancing transcriptional activity, suppressing ER stress and promoting Foxo1 degradation, compared to that of wild type XBP1s (WT). Consistently, overexpression of the K60/77R XBP1s mutant in DIO mice increased the ability to reduce ER stress and decrease Foxo1 levels, thus contributed to maintaining glucose homeostasis. CONCLUSION Our results suggest that delaying the degradation of XBP1s by preventing ubiquitination might provide a strategic approach for reducing ER stress as an anti-diabetes therapy.

中文翻译:

抑制XBP1s泛素化可增强其蛋白质稳定性并改善葡萄糖稳态。

背景技术肝内质网应激是胰岛素抵抗和2型糖尿病的危险因素。X-box结合蛋白1剪接(XBP1s)是一种转录因子,在改善胰岛素抵抗和维持葡萄糖稳态方面起着关键作用。不幸的是,该蛋白的半衰期短,阻碍了其临床应用,而赖氨酸残基的特定位点可能被泛素化并参与XBP1s的降解仍然难以捉摸。方法和结果在这里,我们确定了XBP1s上的K60和K77是其蛋白酶体依赖性降解所需的两个关键泛素位点。我们还构建了XBP1s(K60 / 77R)的双突变体形式,发现它具有更高的抵抗泛素介导的蛋白质降解,增加核转运,增强转录活性的能力。与野生型XBP1s(WT)相比,可抑制ER应激并促进Foxo1降解。一致地,在DIO小鼠中K60 / 77R XBP1s突变体的过表达增加了减少ER应激和降低Foxo1水平的能力,从而有助于维持葡萄糖稳态。结论我们的结果表明,通过防止泛素化来延迟XBP1s的降解可能为减少ER应激提供了一种战略方法,作为一种抗糖尿病疗法。
更新日期:2019-12-17
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