Peptide hormones are crucial regulators of many aspects of human physiology. Mutations that alter these signaling peptides are associated with physiological imbalances that underlie diseases. However, the conformational maturation of peptide hormone precursors (prohormones) in the ER remains largely unexplored. Here, we report that conformational maturation of proAVP, the precursor for the antidiuretic hormone arginine-vasopressin, within the ER requires the ER-associated degradation (ERAD) activity of the Sel1L-Hrd1 protein complex. Serum hyperosmolality induces expression of both ERAD components and proAVP in AVP-producing neurons. Mice with global or AVP neuron–specific ablation of Se1L-Hrd1 ERAD progressively developed polyuria and polydipsia, characteristics of diabetes insipidus. Mechanistically, we found that ERAD deficiency causes marked ER retention and aggregation of a large proportion of all proAVP protein. Further, we show that proAVP is an endogenous substrate of Sel1L-Hrd1 ERAD. The inability to clear misfolded proAVP with highly reactive cysteine thiols in the absence of Sel1L-Hrd1 ERAD causes proAVP to accumulate and participate in inappropriate intermolecular disulfide–bonded aggregates, promoted by the enzymatic activity of protein disulfide isomerase (PDI). This study highlights a pathway linking ERAD to prohormone conformational maturation in neuroendocrine cells, expanding the role of ERAD in providing a conducive ER environment for nascent proteins to reach proper conformation.

中文翻译：

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血管加压素原激素处理和全身水稳态需要与ER相关的降解

肽激素是人类生理学许多方面的关键调节剂。改变这些信号肽的突变与导致疾病的生理失衡有关。然而，ER中肽激素前体（激素）的构象成熟仍未开发。在这里，我们报道ER中抗利尿激素精氨酸-加压素的前体proAVP的构象成熟需要Sel1L-Hrd1蛋白复合体的ER相关降解（ERAD）活性。血清高渗性会在产生AVP的神经元中诱导ERAD成分和proAVP的表达。Se1L-Hrd1 ERAD整体或AVP神经元特异性消融的小鼠逐渐发展为多尿和多饮，这是尿崩症的特征。机械上，我们发现，ERAD缺乏会导致明显的ER保留和大部分proAVP蛋白的聚集。此外，我们显示proAVP是Sel1L-Hrd1 ERAD的内源性底物。在缺少Sel1L-Hrd1 ERAD的情况下，无法用高反应性半胱氨酸巯基清除错折叠的proAVP，会导致proAVP积聚并参与不合适的分子间二硫键键合的聚集体，这是由蛋白质二硫键异构酶（PDI）的酶促活性促进的。这项研究突出了将ERAD与神经内分泌细胞中激素原构象成熟联系起来的途径，扩大了ERAD在为新生蛋白质达到适当构象提供有利的ER环境中的作用。在缺少Sel1L-Hrd1 ERAD的情况下，无法清除具有高反应性半胱氨酸硫醇的错误折叠的proAVP，会导致proAVP积聚并参与不合适的分子间二硫键键合的聚集体，这是由于蛋白质二硫键异构酶（PDI）的酶促活性所促进的。这项研究突出了将ERAD与神经内分泌细胞中激素原构象成熟联系起来的途径，扩大了ERAD在为新生蛋白质达到适当构象提供有利的ER环境中的作用。在缺少Sel1L-Hrd1 ERAD的情况下，无法用高反应性半胱氨酸巯基清除错折叠的proAVP，会导致proAVP积聚并参与不合适的分子间二硫键键合的聚集体，这是由蛋白质二硫键异构酶（PDI）的酶促活性促进的。这项研究突出了将ERAD与神经内分泌细胞中激素原构象成熟联系起来的途径，扩大了ERAD在为新生蛋白质达到适当构象提供有利的ER环境中的作用。