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Mol Cell. 2013 Oct 10;52(1):75-86. doi: 10.1016/j.molcel.2013.08.038. Epub 2013 Sep 26.

SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency.

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  • 1Laboratory of Cell Signaling, Graduate School of Pharmaceutical Sciences, Global Center of Education and Research for Chemical Biology of the Diseases, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.


Zinc is an essential trace element, and impaired zinc homeostasis is implicated in the pathogenesis of various human diseases. However, the mechanisms cells use to respond to zinc deficiency are poorly understood. We previously reported that amyotrophic lateral sclerosis (ALS)-linked pathogenic mutants of SOD1 cause chronic endoplasmic reticulum (ER) stress through specific interactions with Derlin-1, which is a component of the ER-associated degradation machinery. Moreover, we recently demonstrated that this interaction is common to ALS-linked SOD1 mutants, and wild-type SOD1 (SOD1(WT)) comprises a masked Derlin-1 binding region (DBR). Here, we found that, under zinc-deficient conditions, SOD1(WT) adopts a mutant-like conformation that exposes the DBR and induces the homeostatic ER stress response, including the inhibition of protein synthesis and induction of a zinc transporter. We conclude that SOD1 has a function as a molecular switch that activates the ER stress response, which plays an important role in cellular homeostasis under zinc-deficient conditions.

Copyright © 2013 Elsevier Inc. All rights reserved.

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