Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis
Guojun Shi, … , Martin Spiess, Ling Qi
Guojun Shi, … , Martin Spiess, Ling Qi
Published September 18, 2017
Citation Information: J Clin Invest. 2017;127(10):3897-3912. https://doi.org/10.1172/JCI94771.
View: Text | PDF
Research Article Cell biology Endocrinology

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

  • Text
  • PDF
Abstract

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.

Authors

Guojun Shi, Diane R.M. Somlo, Geun Hyang Kim, Cristina Prescianotto-Baschong, Shengyi Sun, Nicole Beuret, Qiaoming Long, Jonas Rutishauser, Peter Arvan, Martin Spiess, Ling Qi

×

Figure 1

Mice with globally induced Sel1L deficiency develop central diabetes insipidus.

Options: View larger image (or click on image) Download as PowerPoint
Mice with globally induced Sel1L deficiency develop central diabetes ins...
(A) Representative images of cages housing WT (Sel1Lf/f) and inducible KO (Sel1LERCre) mice 3 days after changing to fresh bedding. Circle and arrows indicate the wet spot. Arrows indicate damp bedding. (B) Metabolic cage analysis of 24-hour water intake by Sel1Lfl/fl and Sel1LERCre mice on day 11 or 12 after tamoxifen administration (n = 4 mice/group). (C and D) Progressive changes in water intake (C) and urine output (D) in Sel1Lfl/fl and Sel1LERCre mice after tamoxifen treatment (indicated by 3 arrows). n = 6 mice each group. (E) Urine osmolality 2 weeks after tamoxifen treatment. (F) Representative fluorescence images of Aquaporin 2 (AQP2, red) in the kidney collecting duct cells of Sel1Lfl/fl and Sel1LERCre mice 1 week after tamoxifen treatment, either before (control) or 30 minutes after dDAVP injections. (G) Response to the AVP receptor agonist dDAVP in Sel1Lfl/fl and Sel1LERCre mice 2 weeks after tamoxifen administration. Urine osmolality before and after administration is shown (n = 3 each group). †P < 0.05, and †††P < 0.001, by paired Student’s t test, showing that both Sel1Lfl/fl and Sel1LERCre mice responded to dDAVP with significant increases in osmolality. ##P < 0.01, by 2-way ANOVA analysis, showing a differential response to dDAVP in Sel1Lfl/fl and Sel1LERCre mice. (H) Serum AVP levels 2 weeks after tamoxifen treatment. Values represent the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by Student’s t test (B–E and H). Data represent at least 2 independent experiments.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts