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Regulated increase in folding capacity prevents unfolded protein stress in the ER.

ABSTRACT: Stimulation of thyrocytes with thyroid stimulating hormone (TSH) leads to a morphological change and a massive increase in thyroglobulin (Tg) production. Although Tg is a demanding client of the endoplasmic reticulum (ER), its increase did not result in significant accumulation of unfolded protein in the ER. Instead, ER chaperones and folding enzymes reached maximum synthesis rates immediately after TSH stimulation, before significant upregulation of Tg synthesis. The resulting increase in folding capacity before client protein production prevented cellular unfolded-protein stress, confirmed by the silence of the most conserved branch of the unfolded protein response. Thyrocytes set an example of physiological adaptation of cells to a future potentially stress-causing situation, which suggests a general strategy for both non-secretory and specialized secretory cells.

SUBMITTER: Christis C

PROVIDER: S-EPMC2823579 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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Regulated increase in folding capacity prevents unfolded protein stress in the ER.

Christis Chantal C Fullaondo Asier A Schildknegt Danny D Mkrtchian Souren S Heck Albert J R AJ Braakman Ineke I

Journal of cell science 20100209 Pt 5

Stimulation of thyrocytes with thyroid stimulating hormone (TSH) leads to a morphological change and a massive increase in thyroglobulin (Tg) production. Although Tg is a demanding client of the endoplasmic reticulum (ER), its increase did not result in significant accumulation of unfolded protein in the ER. Instead, ER chaperones and folding enzymes reached maximum synthesis rates immediately after TSH stimulation, before significant upregulation of Tg synthesis. The resulting increase in foldi ...[more]

PMID: 20144991

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Project description:The endoplasmic reticulum (ER) is the cellular organelle responsible for protein folding and assembly, lipid and sterol biosynthesis, and calcium storage. The unfolded protein response (UPR) is an adaptive intracellular stress response to accumulation of unfolded or misfolded proteins in the ER. In this study, we show that the most conserved UPR sensor inositol-requiring enzyme 1 ? (IRE1?), an ER transmembrane protein kinase/endoribonuclease, is required to maintain hepatic lipid homeostasis under ER stress conditions through repressing hepatic lipid accumulation and maintaining lipoprotein secretion. To elucidate physiological roles of IRE1?-mediated signalling in the liver, we generated hepatocyte-specific Ire1?-null mice by utilizing an albumin promoter-controlled Cre recombinase-mediated deletion. Deletion of Ire1? caused defective induction of genes encoding functions in ER-to-Golgi protein transport, oxidative protein folding, and ER-associated degradation (ERAD) of misfolded proteins, and led to selective induction of pro-apoptotic UPR trans-activators. We show that IRE1? is required to maintain the secretion efficiency of selective proteins. In the absence of ER stress, mice with hepatocyte-specific Ire1? deletion displayed modest hepatosteatosis that became profound after induction of ER stress. Further investigation revealed that IRE1? represses expression of key metabolic transcriptional regulators, including CCAAT/enhancer-binding protein (C/EBP) ?, C/EBP?, peroxisome proliferator-activated receptor ? (PPAR?), and enzymes involved in triglyceride biosynthesis. IRE1? was also found to be required for efficient secretion of apolipoproteins upon disruption of ER homeostasis. Consistent with a role for IRE1? in preventing intracellular lipid accumulation, mice with hepatocyte-specific deletion of Ire1? developed severe hepatic steatosis after treatment with an ER stress-inducing anti-cancer drug Bortezomib, upon expression of a misfolding-prone human blood clotting factor VIII, or after partial hepatectomy. The identification of IRE1? as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries.

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Regulated increase in folding capacity prevents unfolded protein stress in the ER.

Publications

Regulated increase in folding capacity prevents unfolded protein stress in the ER.

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