Insulin and glucagon immunofluorescence staining in mouse pancreatic sections. 
J. Han, R.J. Kaufman (2013) Nat. Cell Bio
Accumulation of unfolded proteins within the ER induces an adaptive stress response known as the unfolded protein response (UPR). The UPR is transduced from the ER lumen to the nucleus by three transmembrane proteins IRE1, ATF6, and PERK. Activation of the UPR induces the production of a family of basic leucine zipper-containing transcription factors that activate transcription of genes encoding functions to reduce the protein-folding load and increase the protein folding capacity of the ER. IRE1 is a serine/threonine protein kinase and endoribonuclease that signals transcriptional activation by initiating a novel splicing reaction on the mRNA encoding the transcription factor XBP1. UPR activation promotes trafficking of ATF6 from the ER to the Golgi where it is processed to yield a cytosolic fragment that is a potent transcriptional activator. Finally, the protein kinase PERK signals translational attenuation through phosphorylation of the alpha subunit of the eukaryotic translation initiation factor 2 (eIF2a) on serine residue 51. This phosphorylation also induces translation of the transcription factor ATF4. We have demonstrated that PERK/eIF2a signaling is essential for glucose-regulated insulin production by pancreatic beta cells, where defects in this pathway result in beta cell dysfunction and diabetes. The findings demonstrate an unprecedented link between glucose metabolism, protein translation, and protein folding and have implications in the treatment of diabetes. Future studies directed to elucidate the molecular logic for the UPR adaptive response will provide fundamental insight into numerous pathological conditions such as viral infection, cancer, inflammation, metabolic disease and atherosclerosis, and protein folding diseases such as Parkinsons disease and Alzheimers disease.

Protein folding is the most error-prone step in gene expression and contributes to all degenerative diseases including neurodegeneration, metabolic syndrome, inflammation and cancer.  Protein misfolding causes protein aggregation that causes cell death.  Unfortunately there is a dearth of information regarding how protein aggregation is controlled in the cell. In a report published in Mol. Biol. Cell, Dr. Kaufman’s lab describes how protein solubility in the endoplasmic reticulum requires a unique enzyme UGGT1, a gene that was first isolated by Dr. Kaufman years ago.  Now the Kaufman lab has demonstrated that this enzyme controls the aggregation of different mutant forms of the protein a-1-antitrypsin(a1-AT), which is produced in the liver.  One mutation in (a1-AT), the Z-allele, is the most common cause of liver failure in children. Kaufman’s studies demonstrate that UGGT1 promotes protein solubility of (a1-AT-Z) and protects cells from death.  The findings provide novel insight into potential avenues to treat and/or prevent the most common devastating liver disease in children.