ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis

Shi, Guojun and Somlo, Diane and Kim, Geun Hyang and Prescianotto-Baschong, Cristina and Sun, Shengyi and Beuret, Nicole and Long, Qiaoming and Rutishauser, Jonas and Arvan, Peter and Spiess, Martin and Qi, Ling. (2017) ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis. Journal of Clinical Investigation, 127 (10). pp. 3897-3912.

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Official URL: http://edoc.unibas.ch/56243/

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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.
Faculties and Departments:05 Faculty of Science
05 Faculty of Science > Departement Biozentrum
05 Faculty of Science > Departement Biozentrum > Growth & Development
05 Faculty of Science > Departement Biozentrum > Former Organization Units Biozentrum > Biochemistry (Spiess)
UniBasel Contributors:Spiess, Martin
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:American Society for Clinical Investigation
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:13 Oct 2017 08:16
Deposited On:13 Oct 2017 08:15

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