Willy Jeffrey A, Young Sara K, Mosley Amber L, Gawrieh Samer, Stevens James L, Masuoka Howard C, Wek Ronald C
From the Departments of Biochemistry and Molecular Biology and Indianapolis, Indiana 46202-5126.
Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5126.
J Biol Chem. 2017 Aug 25;292(34):14050-14065. doi: 10.1074/jbc.M117.799304. Epub 2017 Jul 14.
Nonalcoholic fatty liver disease (steatosis) is the most prevalent liver disease in the Western world. One of the advanced pathologies is nonalcoholic steatohepatitis (NASH), which is associated with induction of the unfolded protein response (UPR) and disruption of autophagic flux. However, the mechanisms by which these processes contribute to the pathogenesis of human diseases are unclear. Herein, we identify the α isoform of the inhibitor of Bruton's tyrosine kinase (IBTKα) as a member of the UPR, whose expression is preferentially translated during endoplasmic reticulum (ER) stress. We found that IBTKα is located in the ER and associates with proteins LC3b, SEC16A, and SEC31A and plays a previously unrecognized role in phagophore initiation from ER exit sites. Depletion of IBTKα helps prevent accumulation of autophagosome intermediates stemming from exposure to saturated free fatty acids and rescues hepatocytes from death. Of note, induction of IBTKα and the UPR, along with inhibition of autophagic flux, was associated with progression from steatosis to NASH in liver biopsies. These results indicate a function for IBTKα in NASH that links autophagy with activation of the UPR.
非酒精性脂肪性肝病（脂肪变性）是西方世界最常见的肝脏疾病。其中一种晚期病变是非酒精性脂肪性肝炎（NASH），它与未折叠蛋白反应（UPR）的诱导和自噬流的破坏有关。然而，这些过程导致人类疾病发病机制尚不清楚。在此，我们确定布鲁顿酪氨酸激酶抑制剂（IBTKα）的α亚型是UPR的成员之一，其表达在内质网（ER）应激期间优先被翻译。我们发现IBTKα定位于内质网，与蛋白质LC3b、SEC16A和SEC31A相关，并在从内质网出口位点起始吞噬泡过程中发挥了之前未被认识的作用。敲除IBTKα有助于防止因暴露于饱和游离脂肪酸而导致的自噬体中间体积累，并拯救肝细胞免于死亡。值得注意的是，在肝活检中，IBTKα和UPR的诱导以及自噬流的抑制与从脂肪变性进展到NASH有关。这些结果表明IBTKα在NASH中具有将自噬与UPR激活联系起来的功能。
