Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response
<p>The 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, wher...
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| مؤلفون آخرون: | , , |
| منشور في: |
2024
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| _version_ | 1864513509762531328 |
|---|---|
| author | Mingzhan Xue (3607649) |
| author2 | Zehra Irshad (18614869) Naila Rabbani (291722) Paul J. Thornalley (291723) |
| author2_role | author author author |
| author_facet | Mingzhan Xue (3607649) Zehra Irshad (18614869) Naila Rabbani (291722) Paul J. Thornalley (291723) |
| author_role | author |
| dc.creator.none.fl_str_mv | Mingzhan Xue (3607649) Zehra Irshad (18614869) Naila Rabbani (291722) Paul J. Thornalley (291723) |
| dc.date.none.fl_str_mv | 2024-01-09T06:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1016/j.redox.2024.103025 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Increased_cellular_protein_modification_by_methylglyoxal_activates_endoplasmic_reticulum-based_sensors_of_the_unfolded_protein_response/26422147 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Unfolded protein response ER stress Hyperglycemia Methylglyoxal Glycation Glycemic disease |
| dc.title.none.fl_str_mv | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>The 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.</p><h2>Other Information</h2> <p> Published in: Redox Biology<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.redox.2024.103025" target="_blank">https://dx.doi.org/10.1016/j.redox.2024.103025</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_3fdbd0dedbe3b73931dd7de705a8b4a5 |
| identifier_str_mv | 10.1016/j.redox.2024.103025 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26422147 |
| publishDate | 2024 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein responseMingzhan Xue (3607649)Zehra Irshad (18614869)Naila Rabbani (291722)Paul J. Thornalley (291723)Biomedical and clinical sciencesClinical sciencesMedical biochemistry and metabolomicsUnfolded protein responseER stressHyperglycemiaMethylglyoxalGlycationGlycemic disease<p>The 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.</p><h2>Other Information</h2> <p> Published in: Redox Biology<br> License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1016/j.redox.2024.103025" target="_blank">https://dx.doi.org/10.1016/j.redox.2024.103025</a></p>2024-01-09T06:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1016/j.redox.2024.103025https://figshare.com/articles/journal_contribution/Increased_cellular_protein_modification_by_methylglyoxal_activates_endoplasmic_reticulum-based_sensors_of_the_unfolded_protein_response/26422147CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/264221472024-01-09T06:00:00Z |
| spellingShingle | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response Mingzhan Xue (3607649) Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Unfolded protein response ER stress Hyperglycemia Methylglyoxal Glycation Glycemic disease |
| status_str | publishedVersion |
| title | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| title_full | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| title_fullStr | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| title_full_unstemmed | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| title_short | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| title_sort | Increased cellular protein modification by methylglyoxal activates endoplasmic reticulum-based sensors of the unfolded protein response |
| topic | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics Unfolded protein response ER stress Hyperglycemia Methylglyoxal Glycation Glycemic disease |