The endoplasmic reticulum (ER) responds to the accumulation of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways - cumulatively called the unfolded protein response (UPR). Together, at least three mechanistically distinct arms of the UPR regulate the expression of numerous genes that function within the secretory pathway but also affect broad aspects of cell fate and the metabolism of proteins, amino acids and lipids. The arms of the UPR are integrated to provide a response that remodels the secretory apparatus and aligns cellular physiology to the demands imposed by ER stress.

Signal integration in the endoplasmic reticulum unfolded protein response

Protein-folding stress at the endoplasmic reticulum (ER) is a salient feature of specialized secretory cells and is also involved in the pathogenesis of many human diseases. ER stress is buffered by the activation of the unfolded protein response (UPR), a homeostatic signalling network that orchestrates the recovery of ER function, and failure to adapt to ER stress results in apoptosis. Progress in the field has provided insight into the regulatory mechanisms and signalling crosstalk of the three branches of the UPR, which are initiated by the stress sensors protein kinase RNA-like ER kinase (PERK), inositol-requiring protein 1α (IRE1α) and activating transcription factor 6 (ATF6). In addition, novel physiological outcomes of the UPR that are not directly related to protein-folding stress, such as innate immunity, metabolism and cell differentiation, have been revealed.

The unfolded protein response: controlling cell fate decisions under ER stress and beyond

Anthracyclin-treated tumor cells are particularly effective in eliciting an anticancer immune response, whereas other DNA-damaging agents such as etoposide and mitomycin C do not induce immunogenic cell death. Here we show that anthracyclins induce the rapid, preapoptotic translocation of calreticulin (CRT) to the cell surface. Blockade or knockdown of CRT suppressed the phagocytosis of anthracyclin-treated tumor cells by dendritic cells and abolished their immunogenicity in mice. The anthracyclin-induced CRT translocation was mimicked by inhibition of the protein phosphatase 1/GADD34 complex. Administration of recombinant CRT or inhibitors of protein phosphatase 1/GADD34 restored the immunogenicity of cell death elicited by etoposide and mitomycin C, and enhanced their antitumor effects in vivo. These data identify CRT as a key feature determining anticancer immune responses and delineate a possible strategy for immunogenic chemotherapy.

Calreticulin exposure dictates the immunogenicity of cancer cell death

Endoplasmic Reticulum Stress and the Inflammatory Basis of Metabolic Disease

The ability to respond to perturbations in endoplasmic reticulum (ER) function is a fundamentally important property of all cells, but ER stress can also lead to apoptosis. In settings of chronic ER stress, the associated apoptosis may contribute to pathophysiological processes involved in a number of prevalent diseases, including neurodegenerative diseases, diabetes, atherosclerosis and renal disease. The molecular mechanisms linking ER stress to apoptosis are the topic of this review, with emphases on relevance to pathophysiology and integration and complementation among the various apoptotic pathways induced by ER stress.

/pdf/integrating-the-mechanisms-of-apoptosis-induced-by-41jc3ygt5o.pdf

Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress.

Most protein phosphatases have little intrinsic substrate specificity, making selective pharmacological inhibition of specific dephosphorylation reactions a challenging problem. In a screen for small molecules that protect cells from endoplasmic reticulum (ER) stress, we identified salubrinal, a selective inhibitor of cellular complexes that dephosphorylate eukaryotic translation initiation factor 2 subunit alpha (eIF2alpha). Salubrinal also blocks eIF2alpha dephosphorylation mediated by a herpes simplex virus protein and inhibits viral replication. These results suggest that selective chemical inhibitors of eIF2alpha dephosphorylation may be useful in diseases involving ER stress or viral infection. More broadly, salubrinal demonstrates the feasibility of selective pharmacological targeting of cellular dephosphorylation events.

https://science.sciencemag.org/content/sci/307/5711/935.full.pdf

A Selective Inhibitor of eIF2α Dephosphorylation Protects Cells from ER Stress

Total synthesis and cytotoxicity studies of a cyclic depsipeptide with proposed structure of palau'amide.

Structure-activity relationship studies of salubrinal lead to its active biotinylated derivative.

The synthesis and structure-activity relationships (SAR) of salubrinal, a small molecule that protects cells from apoptosis induced by endoplasmic reticulum (ER) stress, are described. It is revealed that the trichloromethyl group greatly contributes to the activity. Based on the SAR results, salubrinal was converted into a biotinylated derivative which retains activity and can be used as a biological tool for target identification.

Structure—Activity Relationship Studies of Salubrinal Lead to Its Active Biotinylated Derivative.

INTRODUCTION
Adipogenesis, a highly coordinated process regulated by numerous effectors, is largely responsible for the quantity and size of adipocytes. Attenuation of adipocyte differentiation has been proposed as a viable technique for reducing obesity and its associated diseases. microRNAs play an important role in human bone marrow mesenchymal stem cells (hMSCs) adipogenic differentiation. However, there is a lack of clarity regarding the role of miR-328-5p in adipogenesis.


MATERIAL AND METHODS
Using the lentiviral vectors to overexpress fatty acid synthase (FASN) and miR-328-5p, RT-qPCR and Western blotting were carried out to assess RNA expression and protein levels of FASN and adipogenic marker factors. Meanwhile, Oil red O staining and lipid quantification was performed to evaluate the accumulation of intracellular lipid droplets. Additionally, the validity of FASN as a potential target gene for miR-328-5p was carried out using a luciferase reporter assay.


RESULTS
Our data showed that hMSCs adipogenic differentiation was associated with the reduced miR-328-5p expression, while an elevated expression of the underlined miRNA attenuated adipogenesis and the expression of adipogenic marker genes. Luciferase reporter assay validated FASN as a target gene of miR-328-5p, and an elevated FASN expression reversed the anti-adipogenic effects of miR-328-5p.


CONCLUSIONS
The results revealed that miR-328-5p inhibits hMSCs adipogenic differentiation by targeting FASN. These findings contribute to our understanding of obesity-related disease development.

MiR-328-5p inhibits the adipogenic differentiation of hMSCs by targeting FASN.

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