TY - JOUR
T1 - High ER stress in β-cells stimulates intracellular degradation of misfolded insulin
AU - Allen, Jenny R.
AU - Nguyen, Linh X.
AU - Sargent, Karen E.G.
AU - Lipson, Kathryn L.
AU - Hackett, Anthony
AU - Urano, Fumihiko
N1 - Funding Information:
We thank Dr. Keiji Tanaka for ubiquitin expression vectors and Dr. Seiichi Oyadomari and Hideki Nishitoh for insulin expression vectors. We also thank Dr. Aldo Rossini, Dr. Rita Bortell, Jeanne Cole, Dr. Ian York, and Dr. Tomohiko Urano for comments on the manuscript. This work was supported by NIH Grant DK32520, a Worcester Foundation grant, and Juvenile Diabetes Research Foundation Innovative Grant to F. Urano.
PY - 2004/11/5
Y1 - 2004/11/5
N2 - Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, elicits an adaptive response, the unfolded protein response (UPR). One component of the UPR, the endoplasmic reticulum-associated protein degradation (ERAD) system, has an important function in the survival of ER stressed cells. Here, we show that HRD1, a component of the ERAD system, is upregulated in pancreatic islets of the Akita diabetes mouse model and enhances intracellular degradation of misfolded insulin. High ER stress in β-cells stimulated mutant insulin degradation through HRD1 to protect β-cells from ER stress and ensuing death. If HRD1 serves the same function in humans, it may serve as a target for therapeutic intervention in diabetes.
AB - Endoplasmic reticulum (ER) stress, which is caused by the accumulation of misfolded proteins in the ER, elicits an adaptive response, the unfolded protein response (UPR). One component of the UPR, the endoplasmic reticulum-associated protein degradation (ERAD) system, has an important function in the survival of ER stressed cells. Here, we show that HRD1, a component of the ERAD system, is upregulated in pancreatic islets of the Akita diabetes mouse model and enhances intracellular degradation of misfolded insulin. High ER stress in β-cells stimulated mutant insulin degradation through HRD1 to protect β-cells from ER stress and ensuing death. If HRD1 serves the same function in humans, it may serve as a target for therapeutic intervention in diabetes.
KW - Diabetes
KW - Endoplasmic reticulum stress
KW - Endoplasmic-reticulum associated protein degradation
KW - Unfolded protein response
UR - https://www.scopus.com/pages/publications/4744374044
U2 - 10.1016/j.bbrc.2004.09.035
DO - 10.1016/j.bbrc.2004.09.035
M3 - Article
C2 - 15464997
AN - SCOPUS:4744374044
SN - 0006-291X
VL - 324
SP - 166
EP - 170
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -