TY - JOUR
T1 - Endoplasmic reticulum stress and N-glycosylation modulate expression of WFS1 protein
AU - Yamaguchi, Suguru
AU - Ishihara, Hisamitsu
AU - Tamura, Akira
AU - Yamada, Takahiro
AU - Takahashi, Rui
AU - Takei, Daisuke
AU - Katagiri, Hideki
AU - Oka, Yoshitomo
N1 - Funding Information:
We are grateful to Y. Nagura for her expert technical assistance. This work was supported by a grant from Suzuken Memorial Foundation to H.I. and a Grant-in-Aid for Scientific Research (13204062) to Y.O. from the Ministry of Education, Science, Sports and Culture of Japan.
PY - 2004/12/3
Y1 - 2004/12/3
N2 - Mutations of the WFS1 gene are responsible for two hereditary diseases, Wolfram syndrome and low frequency sensorineural hearing loss. The WFS1 protein is a glycoprotein located in the endoplasmic reticulum (ER) membrane but its function is poorly understood. Herein we show WFS1 mRNA and protein levels in pancreatic islets to be increased with ER-stress inducers, thapsigargin and dithiothreitol. Another ER-stress inducer, the N-glycosylation inhibitor tunicamycin, also raised WFS1 mRNA but not protein levels. Site-directed mutagenesis showed both Asn-663 and Asn-748 to be N-glycosylated in mouse WFS1 protein. The glycosylation-defective WFS1 protein, in which Asn-663 and Asn-748 had been substituted with aspartate, exhibited an increased protein turnover rate. Consistent with this, the WFS1 protein was more rapidly degraded in the presence of tunicamycin. These data indicate that ER-stress and N-glycosylation play important roles in WFS1 expression and stability, and also suggest regulatory roles for this protein in ER-stress induced cell death.
AB - Mutations of the WFS1 gene are responsible for two hereditary diseases, Wolfram syndrome and low frequency sensorineural hearing loss. The WFS1 protein is a glycoprotein located in the endoplasmic reticulum (ER) membrane but its function is poorly understood. Herein we show WFS1 mRNA and protein levels in pancreatic islets to be increased with ER-stress inducers, thapsigargin and dithiothreitol. Another ER-stress inducer, the N-glycosylation inhibitor tunicamycin, also raised WFS1 mRNA but not protein levels. Site-directed mutagenesis showed both Asn-663 and Asn-748 to be N-glycosylated in mouse WFS1 protein. The glycosylation-defective WFS1 protein, in which Asn-663 and Asn-748 had been substituted with aspartate, exhibited an increased protein turnover rate. Consistent with this, the WFS1 protein was more rapidly degraded in the presence of tunicamycin. These data indicate that ER-stress and N-glycosylation play important roles in WFS1 expression and stability, and also suggest regulatory roles for this protein in ER-stress induced cell death.
KW - ER-stress
KW - Low frequency sensorineural hearing loss
KW - N-Glycosylation
KW - WFSI
KW - Wolfram syndrome
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U2 - 10.1016/j.bbrc.2004.10.017
DO - 10.1016/j.bbrc.2004.10.017
M3 - Article
C2 - 15522226
AN - SCOPUS:7444231569
VL - 325
SP - 250
EP - 256
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 1
ER -