TY - JOUR
T1 - Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells
AU - Fonseca, Sonya G.
AU - Ishigaki, Shinsuke
AU - Oslowski, Christine M.
AU - Lu, Simin
AU - Lipson, Kathryn L.
AU - Ghosh, Rajarshi
AU - Hayashi, Emiko
AU - Ishihara, Hisamitsu
AU - Oka, Yoshitomo
AU - Permutt, M. Alan
AU - Urano, Fumihiko
PY - 2010/3/1
Y1 - 2010/3/1
N2 - Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of β cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6α (ATF6α), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6α target genes and repressed ATF6α-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6α to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, β cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6α and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic β cell death in diabetes.
AB - Wolfram syndrome is an autosomal-recessive disorder characterized by insulin-dependent diabetes mellitus, caused by nonautoimmune loss of β cells, and neurological dysfunctions. We have previously shown that mutations in the Wolfram syndrome 1 (WFS1) gene cause Wolfram syndrome and that WFS1 has a protective function against ER stress. However, it remained to be determined how WFS1 mitigates ER stress. Here we have shown in rodent and human cell lines that WFS1 negatively regulates a key transcription factor involved in ER stress signaling, activating transcription factor 6α (ATF6α), through the ubiquitin-proteasome pathway. WFS1 suppressed expression of ATF6α target genes and repressed ATF6α-mediated activation of the ER stress response element (ERSE) promoter. Moreover, WFS1 stabilized the E3 ubiquitin ligase HRD1, brought ATF6α to the proteasome, and enhanced its ubiquitination and proteasome-mediated degradation, leading to suppression of ER stress signaling. Consistent with these data, β cells from WFS1-deficient mice and lymphocytes from patients with Wolfram syndrome exhibited dysregulated ER stress signaling through upregulation of ATF6α and downregulation of HRD1. These results reveal a role for WFS1 in the negative regulation of ER stress signaling and in the pathogenesis of diseases involving chronic, unresolvable ER stress, such as pancreatic β cell death in diabetes.
UR - http://www.scopus.com/inward/record.url?scp=77949751415&partnerID=8YFLogxK
U2 - 10.1172/JCI39678
DO - 10.1172/JCI39678
M3 - Article
C2 - 20160352
AN - SCOPUS:77949751415
VL - 120
SP - 744
EP - 755
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 3
ER -