The Unfolded Protein Response: A Pathway That Links Insulin Demand with β-Cell Failure and Diabetes
Donalyn Scheuner and
Randal J. Kaufman
Departments of Biological Chemistry (D.S., R.J.K.) and Internal Medicine (R.J.K.), and Howard Hughes Medical Institute (R.J.K.), The University of Michigan Medical Center, Ann Arbor, Michigan 48109
Correspondence: Address all correspondence and requests for reprints to: Randal J. Kaufman, Departments of Biological Chemistry and Internal Medicine, and Howard Hughes Medical Institute, The University of Michigan Medical Center, Ann Arbor, Michigan 48109. E-mail: scheuner{at}umich.edu or kaufmanr{at}umich.edu
The endoplasmic reticulum (ER) is the entry site into the secretorypathway for newly synthesized proteins destined for the cellsurface or released into the extracellular milieu. The studyof protein folding and trafficking within the ER is an extremelyactive area of research that has provided novel insights intomany disease processes. Cells have evolved mechanisms to modulatethe capacity and quality of the ER protein-folding machineryto prevent the accumulation of unfolded or misfolded proteins.These signaling pathways are collectively termed the unfoldedprotein response (UPR). The UPR sensors signal a transcriptionalresponse to expand the ER folding capacity, increase degredationof malfolded proteins, and limit the rate of mRNA translationto reduce the client protein load. Recent genetic and biochemicalevidence in both humans and mice supports a requirement forthe UPR to preserve ER homeostasis and prevent the β-cellfailure that may be fundamental in the etiology of diabetes.Chronic or overwhelming ER stress stimuli associated with metabolicsyndrome can disrupt protein folding in the ER, reduce insulinsecretion, invoke oxidative stress, and activate cell deathpathways. Therapeutic interventions to prevent polypeptide-misfolding,oxidative damage, and/or UPR-induced cell death have the potentialto improve β-cell function and/or survival in the treatmentof diabetes.
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