Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA.
J Biol Chem. 2011 Oct 28;286(43):37602-14. doi: 10.1074/jbc.M111.284794. Epub 2011 Aug 20.
Quality control of endoplasmic reticulum proteins involves the identification and engagement of misfolded proteins, dislocation of the misfolded protein across the endoplasmic reticulum (ER) membrane, and ubiquitin-mediated targeting to the proteasome for degradation. Ancient ubiquitous protein 1 (AUP1) physically associates with the mammalian HRD1-SEL1L complex, and AUP1 depletion impairs degradation of misfolded ER proteins. One of the functions of AUP1 in ER quality control is to recruit the soluble E2 ubiquitin-conjugating enzyme UBE2G2. We further show that the CUE domain of AUP1 regulates polyubiquitylation and facilitates the interaction of AUP1 with the HRD1 complex and with dislocation substrates. AUP1 localizes both to the ER and to lipid droplets. The AUP1 expression level affects the abundance of cellular lipid droplets and as such represents the first protein with lipid droplet regulatory activity to be linked to ER quality control. These findings indicate a possible connection between ER protein quality control and lipid droplets.
内质网蛋白质的质量控制涉及到错误折叠蛋白质的识别和结合，错误折叠蛋白穿过内质网（ER）膜的易位，以及泛素介导的靶向蛋白酶体进行降解。古老普遍存在的蛋白 1（AUP1）与哺乳动物 HRD1-SEL1L 复合物物理结合，AUP1 耗竭会损害错误折叠 ER 蛋白的降解。AUP1 在 ER 质量控制中的一个功能是招募可溶性 E2 泛素连接酶 UBE2G2。我们进一步表明，AUP1 的 CUE 结构域调节多泛素化，并促进 AUP1 与 HRD1 复合物以及与易位底物的相互作用。AUP1 定位于内质网和脂滴。AUP1 的表达水平影响细胞脂滴的丰度，因此它是第一个与 ER 质量控制相关的具有脂滴调节活性的蛋白质。这些发现表明 ER 蛋白质质量控制和脂滴之间可能存在联系。
