TY - JOUR
T1 - SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency
AU - Homma, Kengo
AU - Fujisawa, Takao
AU - Tsuburaya, Naomi
AU - Yamaguchi, Namiko
AU - Kadowaki, Hisae
AU - Takeda, Kohsuke
AU - Nishitoh, Hideki
AU - Matsuzawa, Atsushi
AU - Naguro, Isao
AU - Ichijo, Hidenori
N1 - Funding Information:
We thank K. Mori for providing the GRP78 promoter plasmid. We also thank all of the Laboratory of Cell Signaling members for valuable discussions. A portion of this study resulted from “Understanding of molecular and environmental bases for brain health” performed under the Strategic Research Program for Brain Sciences by the Ministry of Education, Culture, Sports, Science and Technology of Japan. This study was also supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Advanced Research for Medical Products Mining Programme of the National Institute of Biomedical Innovation as well as the Tokyo Biochemical Research Foundation, Takeda Science Foundation, Uehara Memorial Foundation, Suzuken Memorial Foundation, Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Nakabayashi Trust for ALS Research.
PY - 2013/10/10
Y1 - 2013/10/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.molcel.2013.08.038
DO - 10.1016/j.molcel.2013.08.038
M3 - Article
C2 - 24076220
AN - SCOPUS:84885382830
VL - 52
SP - 75
EP - 86
JO - Molecular Cell
JF - Molecular Cell
SN - 1097-2765
IS - 1
ER -
