Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus
Daniel G. Bichet, Yoann Lussier
Daniel G. Bichet, Yoann Lussier
Published September 18, 2017
Citation Information: J Clin Invest. 2017;127(10):3591-3593. https://doi.org/10.1172/JCI96839.
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Commentary

Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus

Abstract

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.

Authors

Daniel G. Bichet, Yoann Lussier

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Figure 1

Misfolded and mutant proAVP are Sel1L substrates that are targeted for ER-association degradation.

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Misfolded and mutant proAVP are Sel1L substrates that are targeted for E...
(A) Representation of a monomeric structure of proAVP with eight disulfide bridges. (B) The conformational maturation of the AVP precursor proAVP within the ER requires ERAD activity of the SEL1L-HRD1 protein complex. Misfolded proAVP is recruited to the ERAD complex via the activity of various ER chaperones such as binding Ig protein (BiP), ER degradation–enhancing α-mannosidase–like protein (EDEM), osteosarcoma amplified 9 (OS9), and XTP3-transactivated gene B protein (XTP3B) for cytosolic degradation. SEL1L–HRD1 is part of an E3 ligase–coupled dislocation complex that integrates the coupled processes of substrate ubiquitination (Ub), membrane extraction via VCP/p97, and proteolytic destruction by the 26S proteasome (5, 13).