SOD1 as a molecular switch for initiating the homeostatic ER stress response under zinc deficiency.
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.
Laboratory 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.
Kengo
K
Homma
Takao
T
Fujisawa
Naomi
N
Tsuburaya
Namiko
N
Yamaguchi
Hisae
H
Kadowaki
Kohsuke
K
Takeda
Hideki
H
Nishitoh
Atsushi
A
Matsuzawa
Isao
I
Naguro
Hidenori
H
Ichijo
D001665:Binding Sites; D027682:Cation Transport Proteins / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D059865:Endoplasmic Reticulum Stress; D057809:HEK293 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006706:Homeostasis; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D034622:RNA Interference; D015398:Signal Transduction; D013329:Structure-Activity Relationship; D013482:Superoxide Dismutase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000072105:Superoxide Dismutase-1; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D015032:Zinc / Q000172:deficiency*
D027682:Cation Transport Proteins; C487709:DERL1 protein, human; D008565:Membrane Proteins; C497524:SLC39A14 protein, human; C000606290:SOD1 protein, human; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D015032:Zinc