Crosstalk Between the Unfolded Protein Response, MicroRNAs, and Insulin Signaling Pathways: In Search of Biomarkers for the Diagnosis and Treatment of Type 2 Diabetes

Type 2 diabetes is a complex metabolic disorder characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency byβ-cell failure. Even if the mechanisms underlying the pathogenesis ofβ-cell failure are still under investigation, recent increasing genetic, experimental, and clinical evidence indicate that hyperactivation of the unfolded protein response (UPR) to counteract metabolic stresses is closely related toβ-cell dysfunction and apoptosis. Signaling pathways of the UPR are “a double-edged sword” that can promote adaptation or apoptosis depending on the nature of the ER stress condition. In this paper, we summarized our current understanding of the mechanisms and components related to ER stress in theβ-cell pathogenesis of type 2 diabetes.

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HIV protease inhibitor lopinavir-induced TNF-α and IL-6 expression is coupled to the unfolded protein response and ERK signaling pathways in macrophages

Biochemical Pharmacology ◽

10.1016/j.bcp.2009.03.022 ◽

2009 ◽

Vol 78 (1) ◽

pp. 70-77 ◽

Cited By ~ 52

Author(s):

Li Chen ◽

Sirikalaya Jarujaron ◽

Xudong Wu ◽

Lixin Sun ◽

Weibin Zha ◽

...

Keyword(s):

Protease Inhibitor ◽

Unfolded Protein Response ◽

Signaling Pathways ◽

Hiv Protease ◽

Erk Signaling ◽

Hiv Protease Inhibitor ◽

Unfolded Protein ◽

Tnf Α ◽

The Unfolded Protein Response ◽

Protein Response

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Complementary Signaling Pathways Regulate the Unfolded Protein Response and Are Required for C. elegans Development

Cell ◽

10.1016/s0092-8674(01)00612-2 ◽

2001 ◽

Vol 107 (7) ◽

pp. 893-903 ◽

Cited By ~ 450

Author(s):

Xiaohua Shen ◽

Ronald E. Ellis ◽

Kyungho Lee ◽

Chuan-Yin Liu ◽

Kun Yang ◽

...

Keyword(s):

Unfolded Protein Response ◽

Signaling Pathways ◽

C Elegans ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

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The Link between Type 2 Diabetes Mellitus and the Polymorphisms of Glutathione-Metabolizing Genes Suggests a New Hypothesis Explaining Disease Initiation and Progression

Life ◽

10.3390/life11090886 ◽

2021 ◽

Vol 11 (9) ◽

pp. 886

Author(s):

Iuliia Azarova ◽

Elena Klyosova ◽

Alexey Polonikov

Keyword(s):

Type 2 Diabetes ◽

Unfolded Protein Response ◽

Glutathione Synthetase ◽

Beta Cell Apoptosis ◽

Gamma Glutamyl Transferase ◽

Unfolded Protein ◽

Glutamyl Transferase ◽

Protein Response ◽

New Hypothesis

The present study investigated whether type 2 diabetes (T2D) is associated with polymorphisms of genes encoding glutathione-metabolizing enzymes such as glutathione synthetase (GSS) and gamma-glutamyl transferase 7 (GGT7). A total of 3198 unrelated Russian subjects including 1572 T2D patients and 1626 healthy subjects were enrolled. Single nucleotide polymorphisms (SNPs) of the GSS and GGT7 genes were genotyped using the MassArray-4 system. We found that the GSS and GGT7 gene polymorphisms alone and in combinations are associated with T2D risk regardless of sex, age, and body mass index, as well as correlated with plasma glutathione, hydrogen peroxide, and fasting blood glucose levels. Polymorphisms of GSS (rs13041792) and GGT7 (rs6119534 and rs11546155) genes were associated with the tissue-specific expression of genes involved in unfolded protein response and the regulation of proteostasis. Transcriptome-wide association analysis has shown that the pancreatic expression of some of these genes such as EDEM2, MYH7B, MAP1LC3A, and CPNE1 is linked to the genetic risk of T2D. A comprehensive analysis of the data allowed proposing a new hypothesis for the etiology of type 2 diabetes that endogenous glutathione deficiency might be a key condition responsible for the impaired folding of proinsulin which triggered an unfolded protein response, ultimately leading to beta-cell apoptosis and disease development.

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Modulation of the Unfolded Protein Response by the Severe Acute Respiratory Syndrome Coronavirus Spike Protein

Journal of Virology ◽

10.1128/jvi.00659-06 ◽

2006 ◽

Vol 80 (18) ◽

pp. 9279-9287 ◽

Cited By ~ 90

Author(s):

Ching-Ping Chan ◽

Kam-Leung Siu ◽

King-Tung Chin ◽

Kwok-Yung Yuen ◽

Bojian Zheng ◽

...

Keyword(s):

Severe Acute Respiratory Syndrome ◽

Unfolded Protein Response ◽

Signaling Pathways ◽

Transcriptional Activation ◽

Cultured Cells ◽

Protein A ◽

S Protein ◽

Unfolded Protein ◽

The Unfolded Protein Response ◽

Protein Response

ABSTRACT Perturbation of the function of endoplasmic reticulum (ER) causes stress leading to the activation of cell signaling pathways known as the unfolded protein response (UPR). Severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) uses ER as a site for synthesis and processing of viral proteins. In this report, we demonstrate that infection with SARS-CoV induces the UPR in cultured cells. A comparison with M, E, and NSP6 proteins indicates that SARS-CoV spike (S) protein sufficiently induces transcriptional activation of several UPR effectors, including glucose-regulated protein 78 (GRP78), GRP94, and C/EBP homologous protein. A substantial amount of S protein accumulates in the ER. The expression of S protein exerts different effects on the three major signaling pathways of the UPR. Particularly, it induces GRP78/94 through PKR-like ER kinase but has no influence on activating transcription factor 6 or X box-binding protein 1. Taken together, our findings suggest that SARS-CoV S protein specifically modulates the UPR to facilitate viral replication.

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Targeting unfolded protein response in cancer and diabetes

Endocrine Related Cancer ◽

10.1530/erc-15-0106 ◽

2015 ◽

Vol 22 (3) ◽

pp. C1-C4 ◽

Cited By ~ 7

Author(s):

Souren Mkrtchian

Keyword(s):

South Carolina ◽

Unfolded Protein Response ◽

Signal Transduction Pathway ◽

Unfolded Protein ◽

Homologous Protein ◽

Enhancer Binding Protein ◽

Apoptotic Activity ◽

The Unfolded Protein Response ◽

Protein Response

The maturation of secretory and membrane proteins in the endoplasmic reticulum (ER) is tightly regulated by the unfolded protein response (UPR), a signal transduction pathway maintaining ER protein folding homeostasis. However, certain ER states are incompatible with cell survival and therefore the UPR may choose to eliminate severely disrupted cells by apoptosis. This is accomplished primarily through the activation of the transcription factor CCAAT-enhancer-binding protein homologous protein (CHOP). In the April 2015 issue of Endocrine-Related Cancer, researchers from the universities of South Carolina and Athens (Greece) suggested a novel mechanism of CHOP-mediated apoptosis connected with the suppression of a prominent cell cycle regulator with anti-apoptotic activity, p21. These findings and suggested clinical applications, such as potentiation of cancer chemotherapy and a novel therapeutic approach for type 2 diabetes, are discussed in the context of UPR.

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