Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.

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Inflammation and metabolic disorders

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

The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum (ER), where they fold and assemble. Only properly assembled proteins advance from the ER to the cell surface. To ascertain fidelity in protein folding, cells regulate the protein-folding capacity in the ER according to need. The ER responds to the burden of unfolded proteins in its lumen (ER stress) by activating intracellular signal transduction pathways, collectively termed the unfolded protein response (UPR). Together, at least three mechanistically distinct branches of the UPR regulate the expression of numerous genes that maintain homeostasis in the ER or induce apoptosis if ER stress remains unmitigated. Recent advances shed light on mechanistic complexities and on the role of the UPR in numerous diseases.

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The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation

Signal transduction by the JNK group of MAP kinases.

XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor

Endoplasmic reticulum (ER) is a busy cell organelle that participates in many important cellular tasks. It has been established that ER is involved in protein and lipid biosynthesis, calcium regulation, redox regulation, cell signaling, and cell death. Given the many vital and complex functions of ER, there is little wonder that its failure can trigger a range of diseases. Recent genetic and clinical evidence indicates that inherited or acquired dysregulation of ER homeostasis can give rise to genetic diseases, including Wolfram syndrome (which is characterized by juvenile-onset diabetes and neurodegeneration) and a number of common metabolic diseases including diabetes and atherosclerosis. Accelerating interest in the role of ER in metabolic disease has been fueled by recent reports showing pathways that link ER to inflammation. The role of ER as an interface between the immune system and metabolism is an emerging concept (Fig. 1). However, …

https://diabetes.diabetesjournals.org/content/diabetes/63/1/48.full.pdf

Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism

Islet cell hyperplasia in transgenic mice overexpressing EAT/mcl-1, a bcl-2 related gene

The endoplasmic reticulum (ER) lies at the crossroads of protein folding, calcium storage, lipid metabolism, and the regulation of autophagy and apoptosis. Accordingly, dysregulation of ER homeostasis leads to β-cell dysfunction in type 1 and type 2 diabetes that ultimately culminates in cell death. The ER is therefore an emerging target for understanding the mechanisms of diabetes mellitus that captures the complex etiologies of this multifactorial class of metabolic disorders. Our strategy for developing ER-targeted diagnostics and therapeutics is to focus on monogenic forms of diabetes related to ER dysregulation in an effort to understand the exact contribution of ER stress to β-cell death. In this manner, we can develop personalized genetic medicine for ERstress-related diabetic disorders, such as Wolfram syndrome. In this article, we describe the phenotypes and molecular pathogenesis of ERstress-related monogenic forms of diabetes.

Monogenic and syndromic diabetes due to endoplasmic reticulum stress.

Nature 415, 92–96 (2002). In this Letter, the commercial polyclonal antiserum used to detect endogenous XBP-1 was sc-7160 (Santa Cruz Biotechnology) and not sc-8015, as erroneously stated. The antibody sc-8015 is a mouse monoclonal and, in our hands, is not useful in detecting the endogenous proteinby immunoblotting.

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Fumihiko Urano

Papers

Endoplasmic Reticulum: An Interface Between the Immune System and Metabolism

Islet cell hyperplasia in transgenic mice overexpressing EAT/mcl-1, a bcl-2 related gene

Monogenic and syndromic diabetes due to endoplasmic reticulum stress.

corrigendum: IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA

Maternal uniparental disomy of chromosome 4 and homozygous novel mutation in the WFS1 gene in a paediatric patient with Wolfram syndrome.