Endoplasmic Reticulum Stress Interacts With Inflammation in Human Diseases.

The endoplasmic reticulum (ER) is a critical organelle for normal cell function and homeostasis. Disturbance in the protein folding process in the ER, termed ER stress, leads to the activation of unfolded protein response (UPR) that encompasses a complex network of intracellular signaling pathways. The UPR can either restore ER homeostasis or activate pro-apoptotic pathways depending on the type of insults, intensity and duration of the stress, and cell types. ER stress and the UPR have recently been linked to inflammation in a variety of human pathologies including autoimmune, infectious, neurodegenerative, and metabolic disorders. In the cell, ER stress and inflammatory signaling share extensive regulators and effectors in a broad spectrum of biological processes. In spite of different etiologies, the two signaling pathways have been shown to form a vicious cycle in exacerbating cellular dysfunction and causing apoptosis in many cells and tissues. However, the interaction between ER stress and inflammation in many of these diseases remains poorly understood. Further understanding of the biochemistry, cell biology, and physiology may enable the development of novel therapies that spontaneously target these pathogenic pathways.

Endoplasmic reticulum stress in intestinal epithelial cell function and inflammatory bowel disease.

In eukaryotic cells, perturbation of protein folding homeostasis in the endoplasmic reticulum (ER) causes accumulation of unfolded and misfolded proteins in the ER lumen, which activates intracellular signaling pathways termed the unfolded protein response (UPR). Recent studies have linked ER stress and the UPR to inflammatory bowel disease (IBD). The microenvironment of the ER is affected by a myriad of intestinal luminal molecules, implicating ER stress and the UPR in proper maintenance of intestinal homeostasis. Several intestinal cell populations, including Paneth and goblet cells, require robust ER function for protein folding, maturation, and secretion. Prolonged ER stress and impaired UPR signaling may cause IBD through: (1) induction of intestinal epithelial cell apoptosis, (2) disruption of mucosal barrier function, and (3) induction of the proinflammatory response in the gut. Based on our increased understanding of ER stress in IBD, new pharmacological approaches can be developed to improve intestinal homeostasis by targeting ER protein-folding in the intestinal epithelial cells (IECs).

Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease.

SIGNIFICANCE: The endoplasmic reticulum (ER) is a specialized organelle for the folding and trafficking of proteins, which is highly sensitive to changes in intracellular homeostasis and extracellular stimuli. Alterations in the protein-folding environment cause accumulation of misfolded proteins in the ER that profoundly affect a variety of cellular signaling processes, including reduction-oxidation (redox) homeostasis, energy production, inflammation, differentiation, and apoptosis. The unfolded protein response (UPR) is a collection of adaptive signaling pathways that evolved to resolve protein misfolding and restore an efficient protein-folding environment. RECENT ADVANCES: Production of reactive oxygen species (ROS) has been linked to ER stress and the UPR. ROS play a critical role in many cellular processes and can be produced in the cytosol and several organelles, including the ER and mitochondria. Studies suggest that altered redox homeostasis in the ER is sufficient to cause ER stress, which could, in turn, induce the production of ROS in the ER and mitochondria. CRITICAL ISSUES: Although ER stress and oxidative stress coexist in many pathologic states, whether and how these stresses interact is unknown. It is also unclear how changes in the protein-folding environment in the ER cause oxidative stress. In addition, how ROS production and protein misfolding commit the cell to an apoptotic death and contribute to various degenerative diseases is unknown. FUTURE DIRECTIONS: A greater fundamental understanding of the mechanisms that preserve protein folding homeostasis and redox status will provide new information toward the development of novel therapeutics for many human diseases.

Targeting endoplasmic reticulum stress in metabolic disease.

INTRODUCTION: Endoplasmic reticulum (ER) stress, a condition that dramatically affects protein folding homeostasis in cells, has been associated with a number of metabolic diseases. Emerging preclinical and clinical evidence supports the notion that pharmacological modulators of ER stress have therapeutic potential as novel treatments of metabolic disorders. AREAS COVERED: In this review, the molecular mechanisms of ER stress and the unfolded protein response (UPR) in the pathogenesis of metabolic diseases are discussed, highlighting the roles of various UPR components revealed using disease models in mice. Special emphasis is placed on the use of novel small molecules in animal disease models and human pathologies, including type 2 diabetes, obesity, fatty liver disease, and atherosclerosis. EXPERT OPINION: ER stress is a highly promising therapeutic target for metabolic disease. Small molecular chemical chaperones have already demonstrated therapeutic efficacy in animal and human studies. The emergence of compounds that target specific UPR signaling pathways will provide more options for this purpose. Although the findings are promising, more studies are needed to elucidate the efficacy and side effects of these small molecules for future use in humans.

The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice.

BACKGROUND & AIMS: Endoplasmic reticulum (ER) stress has been associated with development of inflammatory bowel disease. We examined the effects of ER stress-induced chaperone response and the orally active chemical chaperones tauroursodeoxycholate (TUDCA) and 4-phenylbutyrate (PBA), which facilitate protein folding and reduce ER stress, in mice with colitis. METHODS: We used dextran sulfate sodium (DSS) to induce colitis in mice that do not express the transcription factor ATF6α or the protein chaperone P58(IPK). We examined the effects of TUDCA and PBA in cultured intestinal epithelial cells (IECs); in wild-type, P58(IPK-/-), and Atf6α(-/-) mice with colitis; and in Il10(-/-) mice. RESULTS: P58(IPK-/-) and Atf6α(-/-) mice developed more severe colitis following administration of DSS than wild-type mice. IECs from P58(IPK-/-) mice had excessive ER stress, and apoptotic signaling was activated in IECs from Atf6α(-/-) mice. Inflammatory stimuli induced ER stress signals in cultured IECs, which were reduced by incubation with TUDCA or PBA. Oral administration of either PBA or TUDCA reduced features of DSS-induced acute and chronic colitis in wild-type mice, the colitis that develops in Il10(-/-) mice, and DSS-induced colitis in P58(IPK-/-) and Atf6α(-/-) mice. Reduced signs of colonic inflammation in these mice were associated with significantly decreased ER stress in colonic epithelial cells. CONCLUSIONS: The unfolded protein response induces expression of genes that encode chaperones involved in ER protein folding; these factors prevent induction of colitis in mice. Chemical chaperones such as TUDCA and PBA alleviate different forms of colitis in mice and might be developed for treatment of inflammatory bowel diseases.

PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling.

BACKGROUND: The dsRNA-activated protein kinase (PKR) phosphorylates the α subunit of eukaryotic translation initiation factor 2 (eIF2α), a global regulator of protein synthesis in mammals. In addition, PKR activates several signal transduction pathways including STAT3 and AKT. PKR is activated by a number of inflammatory stimuli that are induced in the inflamed intestine. In this study we intended to determine the role of PKR in colonic epithelial cells during experimental colitis in mice. METHODS: Age- and sex-matched PKR(+/+,+/-) and PKR(-/-) littermate mice were reconstituted with wildtype bone marrow cells and subjected to dextran sodium sulfate (DSS)-induced colitis. RESULTS: PKR(-/-) mice displayed more severe clinical and histological manifestations upon DSS colitis compared with their PKR(+/+,+/-) littermates. In response to DSS colitis, the colonic epithelial cells of PKR(-/-) mice exhibited impaired activation of the unfolded protein response (UPR) signaling, including eIF2α phosphorylation, endoplasmic reticulum (ER) chaperone response, and ER-associated degradation (ERAD) components, as well as antioxidative stress response. In addition, the phosphorylation of STAT3 and AKT, which are protective against epithelial cell death and colonic inflammation, was also impaired in the colonic epithelial cells of PKR(-/-) mice upon DSS colitis. CONCLUSIONS: These data demonstrate that PKR is a physiologically relevant transducer of inflammatory response signaling in colonic epithelial cells. PKR may promote the homeostasis and survival of intestinal epithelial cells (IECs) through eIF2α-mediated UPR activation, as well as the activation of STAT3 and AKT pathways. In the absence of PKR, the survival and proliferation of IECs was impaired, thus exacerbating intestinal inflammation.

iRhoms: ERADicating the messenger in growth control signaling.

iRhoms are inactive rhomboid-like pseudoproteases that lack essential catalytic residues. Although iRhoms are highly conserved in metazoan species, little is known about their function. In a recent issue of Cell, Zettl et al. (2011) show that iRhoms regulate growth factor signaling through endoplasmic reticulum-associated protein degradation (ERAD).