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المؤلفXue, Mingzhan
المؤلفIrshad, Zehra
المؤلفRabbani, Naila
المؤلفThornalley, Paul J.
تاريخ الإتاحة2024-03-14T07:58:59Z
تاريخ النشر2024-02-01
اسم المنشورRedox Biology
المعرّفhttp://dx.doi.org/10.1016/j.redox.2024.103025
الاقتباسXue, M., Irshad, Z., Rabbani, N., & Thornalley, P. J. (2024). Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response. Redox Biology, 69, 103025.‏
الرقم المعياري الدولي للكتاب22132317
معرّف المصادر الموحدhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85182360421&origin=inward
معرّف المصادر الموحدhttp://hdl.handle.net/10576/53060
الملخصThe unfolded protein response (UPR) detects increased misfolded proteins and activates protein refolding, protein degradation and inflammatory responses. UPR sensors in the endoplasmic reticulum, IRE1α and PERK, bind and are activated by proteins with unexpected surface hydrophobicity, whereas sensor ATF6 is activated by proteolytic cleavage when released from complexation with protein disulfide isomerases (PDIs). Metabolic dysfunction leading to the formation of misfolded proteins with surface hydrophobicity and disruption of ATF6-PDI complexes leading to activation of UPR sensors remains unclear. The cellular concentration of reactive dicarbonyl metabolite, methylglyoxal (MG), is increased in impaired metabolic health, producing increased MG-modified cellular proteins. Herein we assessed the effect of high glucose concentration and related increased cellular MG on activation status of IRE1α, PERK and ATF6. Human aortal endothelial cells and HMEC-1 microvascular endothelial cells were incubated in low and high glucose concentration to model blood glucose control, with increase or decrease of MG by silencing or increasing expression of glyoxalase 1 (Glo1), which metabolizes MG. Increased MG induced by high glucose concentration activated IRE1α, PERK and ATF6 and related downstream signalling leading to increased chaperone, apoptotic and inflammatory gene expression. Correction of increased MG by increasing Glo1 expression prevented UPR activation. MG modification of proteins produces surface hydrophobicity through arginine-derived hydroimidazolone MG-H1 formation, with related protein unfolding and preferentially targets PDIs and chaperone pathways for modification. It thereby poses a major challenge to proteostasis and activates UPR sensors. Pharmacological decrease of MG with Glo1 inducer, trans-resveratrol and hesperetin in combination, offers a novel treatment strategy to counter UPR-related cell dysfunction, particularly in hyperglycemia associated with diabetes.
اللغةen
الناشرElsevier B.V.
الموضوعER stress
Glycation
Glycemic disease
Hyperglycemia
Methylglyoxal
Unfolded protein response
العنوانIncreased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response
النوعArticle
رقم المجلد69
dc.accessType Abstract Only


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