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Uncoupling Proteostasis and Development in Vitro with a Small Molecule Inhibitor of the Pancreatic Endoplasmic Reticulum Kinase, PERK

Harding, Heather P. ; Zyryanova, Alisa F. ; Ron, David

The Journal of biological chemistry, 2012-12, Vol.287 (53), p.44338-44344 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Uncoupling Proteostasis and Development in Vitro with a Small Molecule Inhibitor of the Pancreatic Endoplasmic Reticulum Kinase, PERK
Autor: Harding, Heather P. ; Zyryanova, Alisa F. ; Ron, David
Assuntos: Animals ; Cell Biology ; Cells, Cultured ; eIF-2 Kinase - antagonists & inhibitors ; eIF-2 Kinase - genetics ; eIF-2 Kinase - metabolism ; Endoplasmic Reticulum - drug effects ; Endoplasmic Reticulum - enzymology ; Endoplasmic Reticulum - metabolism ; Endoplasmic Reticulum Stress ; Eukaryotic Initiation Factor-2 - genetics ; Eukaryotic Initiation Factor-2 - metabolism ; Glucose - metabolism ; In Vitro Techniques ; Insulin - chemistry ; Insulin - genetics ; Insulin - metabolism ; Insulin Synthesis ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - enzymology ; Insulin-Secreting Cells - metabolism ; Islets of Langerhans - cytology ; Islets of Langerhans - drug effects ; Islets of Langerhans - enzymology ; Islets of Langerhans - metabolism ; Mice ; Mice, Knockout ; Pancreatic Islets ; Protein Biosynthesis - drug effects ; Protein Folding - drug effects ; Protein Kinase Inhibitors - pharmacology ; Protein Misfolding ; Protein Synthesis ; Rats ; Translation Initiation ; Unfolded Protein Response ; Unfolded Protein Response - drug effects
É parte de: The Journal of biological chemistry, 2012-12, Vol.287 (53), p.44338-44344
Descrição: Loss-of-function mutations in EIF2AK3, encoding the pancreatic endoplasmic reticulum (ER) kinase, PERK, are associated with dysfunction of the endocrine pancreas and diabetes. However, to date it has not been possible to uncouple the long term developmental effects of PERK deficiency from sensitization to physiological levels of ER unfolded protein stress upon interruption of PERK modulation of protein synthesis rates. Here, we report that a selective PERK inhibitor acutely deregulates protein synthesis in freshly isolated islets of Langerhans, across a range of glucose concentrations. Acute loss of the PERK-mediated strand of the unfolded protein response leads to rapid accumulation of misfolded pro-insulin in cultured beta cells and is associated with a kinetic defect in pro-insulin processing. These in vitro observations uncouple the latent role of PERK in beta cell development from the regulation of unfolded protein flux through the ER and attest to the importance of the latter in beta cell proteostasis. PERK controls unfolded protein load in the ER and promotes a latent gene expression program whose relative contributions to cell physiology are incompletely understood. Acute PERK inhibition deregulates protein synthesis and promotes accumulation of misfolded pro-insulin. PERK contributes to proteostasis acutely. The proteostatic activity of PERK can be uncoupled from its latent role in gene expression.
Editor: United States: Elsevier Inc
Idioma: Inglês

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Uncoupling Proteostasis and Development in Vitro with a Small Molecule Inhibitor of the Pancreatic Endoplasmic Reticulum Kinase, PERK

Harding, Heather P. ; Zyryanova, Alisa F. ; Ron, David

United States: Elsevier Inc

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