Bichet Daniel G, Lussier Yoann
Professor of Medicine, Pharmacology and Physiology, University of Montreal, and Nephrology Service, Research Center, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada.
Department of Pharmacology and Physiology, University of Montreal, Montreal, Quebec, Canada.
J Clin Invest. 2017 Oct 2;127(10):3591-3593. doi: 10.1172/JCI96839. Epub 2017 Sep 18.
Deficiency of the antidiuretic hormone arginine vasopressin (AVP) underlies diabetes insipidus, which is characterized by the excretion of abnormally large volumes of dilute urine and persistent thirst. In this issue of the JCI, Shi et al. report that Sel1L-Hrd1 ER-associated degradation (ERAD) is responsible for the clearance of misfolded pro-arginine vasopressin (proAVP) in the ER. Additionally, mice with Sel1L deficiency, either globally or specifically within AVP-expressing neurons, developed central diabetes insipidus. The results of this study demonstrate a role for ERAD in neuroendocrine cells and serve as a clinical example of the effect of misfolded ER proteins retrotranslocated through the membrane into the cytosol, where they are polyubiquitinated, extracted from the ER membrane, and degraded by the proteasome. Moreover, proAVP misfolding in hereditary central diabetes insipidus likely shares common physiopathological mechanisms with proinsulin misfolding in hereditary diabetes mellitus of youth.
抗利尿激素精氨酸加压素(AVP)缺乏是尿崩症的基础,其特征是排出大量异常稀释的尿液并持续口渴。在本期《临床研究杂志》中,Shi等人报告称,Sel1L-Hrd1内质网相关降解(ERAD)负责内质网中错误折叠的前体精氨酸加压素(proAVP)的清除。此外,全身性或特异性在表达AVP的神经元中缺乏Sel1L的小鼠发生了中枢性尿崩症。这项研究的结果证明了ERAD在神经内分泌细胞中的作用,并作为错误折叠的内质网蛋白通过膜逆向转运到细胞质中(在细胞质中它们被多聚泛素化、从内质网膜中提取并被蛋白酶体降解)的影响的一个临床实例。此外,遗传性中枢性尿崩症中的proAVP错误折叠可能与青少年遗传性糖尿病中的胰岛素原错误折叠具有共同的生理病理机制。