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

Kengo Homma, Takao Fujisawa, Naomi Tsuburaya, Namiko Yamaguchi, Hisae Kadowaki, Kohsuke Takeda, Hideki Nishitoh, Atsushi Matsuzawa, Isao Naguro, Hidenori Ichijo

Research output: Contribution to journalArticlepeer-review

99 Citations (Scopus)


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 (SOD1WT) comprises a masked Derlin-1 binding region (DBR). Here, we found that, under zinc-deficient conditions, SOD1WT 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.

Original languageEnglish
Pages (from-to)75-86
Number of pages12
JournalMolecular Cell
Issue number1
Publication statusPublished - 2013 Oct 10


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