High ER stress in beta-cells stimulates intracellular degradation of misfolded insulin.
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 beta-cells stimulated mutant insulin degradation through HRD1 to protect beta-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.
Allen
Jenny R
JR
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Nguyen
Linh X
LX
Sargent
Karen E G
KE
Lipson
Kathryn L
KL
Hackett
Anthony
A
Urano
Fumihiko
F
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003920:Diabetes Mellitus / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000737:chemistry* / Q000378:metabolism*; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D061988:Proteasome Inhibitors; D011487:Protein Conformation; D017510:Protein Folding; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
D007328:Insulin; D061988:Proteasome Inhibitors; D021122:Protein Subunits; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex