DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation
<p>Failure of the heat shock response is a key event that leads to insulin resistance and type 2 diabetes. We recently showed that DNAJB3 co-chaperone is downregulated in obese and diabetic patients and that physical exercise restores its normal expression with a significant improvement of the...
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| المؤلف الرئيسي: | |
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| مؤلفون آخرون: | , , , , , , , |
| منشور في: |
2019
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| الموضوعات: | |
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| _version_ | 1864513554532532224 |
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| author | Abdelilah Arredouani (10914455) |
| author2 | Abdoulaye Diane (14152749) Namat Khattab (14152752) Ilham Bensmail (12204845) Imad Aoude (14152755) Mohamed Chikri (2243) Ramzi Mohammad (3520061) Abdul Badi Abou-Samra (9417977) Mohammed Dehbi (14152758) |
| author2_role | author author author author author author author author |
| author_facet | Abdelilah Arredouani (10914455) Abdoulaye Diane (14152749) Namat Khattab (14152752) Ilham Bensmail (12204845) Imad Aoude (14152755) Mohamed Chikri (2243) Ramzi Mohammad (3520061) Abdul Badi Abou-Samra (9417977) Mohammed Dehbi (14152758) |
| author_role | author |
| dc.creator.none.fl_str_mv | Abdelilah Arredouani (10914455) Abdoulaye Diane (14152749) Namat Khattab (14152752) Ilham Bensmail (12204845) Imad Aoude (14152755) Mohamed Chikri (2243) Ramzi Mohammad (3520061) Abdul Badi Abou-Samra (9417977) Mohammed Dehbi (14152758) |
| dc.date.none.fl_str_mv | 2019-03-18T00:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1038/s41598-019-41244-8 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/DNAJB3_attenuates_metabolic_stress_and_promotes_glucose_uptake_by_eliciting_Glut4_translocation/21598113 |
| 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 DNAJB3 Heat Shock Response Insulin Resistance Type 2 Diabetes Obesity |
| dc.title.none.fl_str_mv | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p>Failure of the heat shock response is a key event that leads to insulin resistance and type 2 diabetes. We recently showed that DNAJB3 co-chaperone is downregulated in obese and diabetic patients and that physical exercise restores its normal expression with a significant improvement of the clinical outcomes. In 3T3-L1 adipocytes, DNAJB3 has a role in improving the sensitivity to insulin and glucose uptake. In co-immunoprecipitation assays, DNAJB3 interacts with both JNK1 and IKKβ kinases. However, the functional impact of such interaction on their activities has not been investigated. Here, we assessed the effect of DNAJB3 on the respective activity of JNK1 and IKKβ in cell-based assays. Using JNK1- and IKKβ-dependent luciferase reporters, we show a marked decrease in luciferase activity by DNAJB3 in response to PMA and TNF-α that was consistent with a decrease in the translocation of p65/NF-κB to the nucleus in response to LPS. Furthermore, TNF-α-mediated IL-6 promoter activation and endogenous mRNA expression are significantly abrogated by DNAJB3 both in 3T3-L1 and C2C12 cells. The ability of DNAJB3 to mitigate ER stress and oxidative stress was also investigated and our data show a significant improvement of both forms of stress. Finally, we examined the effect of overexpressing and knocking down the expression of DNAJB3 on glucose uptake in C2C12 as well as the molecular determinants. Accordingly, we provide evidence for a role of DNAJB3 in promoting both basal and insulin-stimulated glucose uptake. Our finding reveals also a novel role of DNAJB3 in eliciting Glut4 translocation to the plasma membrane. These results suggest a physiological role of DNAJB3 in mitigating metabolic stress and improving glucose homeostasis and could therefore represent a novel therapeutic target for type 2 diabetes.</p><h2>Other Information</h2> <p> Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41598-019-41244-8" target="_blank">http://dx.doi.org/10.1038/s41598-019-41244-8</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_4f7abea833b4549b8da4bb54433af559 |
| identifier_str_mv | 10.1038/s41598-019-41244-8 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/21598113 |
| publishDate | 2019 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocationAbdelilah Arredouani (10914455)Abdoulaye Diane (14152749)Namat Khattab (14152752)Ilham Bensmail (12204845)Imad Aoude (14152755)Mohamed Chikri (2243)Ramzi Mohammad (3520061)Abdul Badi Abou-Samra (9417977)Mohammed Dehbi (14152758)Biomedical and clinical sciencesClinical sciencesMedical biochemistry and metabolomicsDNAJB3Heat ShockResponse Insulin ResistanceType 2 DiabetesObesity<p>Failure of the heat shock response is a key event that leads to insulin resistance and type 2 diabetes. We recently showed that DNAJB3 co-chaperone is downregulated in obese and diabetic patients and that physical exercise restores its normal expression with a significant improvement of the clinical outcomes. In 3T3-L1 adipocytes, DNAJB3 has a role in improving the sensitivity to insulin and glucose uptake. In co-immunoprecipitation assays, DNAJB3 interacts with both JNK1 and IKKβ kinases. However, the functional impact of such interaction on their activities has not been investigated. Here, we assessed the effect of DNAJB3 on the respective activity of JNK1 and IKKβ in cell-based assays. Using JNK1- and IKKβ-dependent luciferase reporters, we show a marked decrease in luciferase activity by DNAJB3 in response to PMA and TNF-α that was consistent with a decrease in the translocation of p65/NF-κB to the nucleus in response to LPS. Furthermore, TNF-α-mediated IL-6 promoter activation and endogenous mRNA expression are significantly abrogated by DNAJB3 both in 3T3-L1 and C2C12 cells. The ability of DNAJB3 to mitigate ER stress and oxidative stress was also investigated and our data show a significant improvement of both forms of stress. Finally, we examined the effect of overexpressing and knocking down the expression of DNAJB3 on glucose uptake in C2C12 as well as the molecular determinants. Accordingly, we provide evidence for a role of DNAJB3 in promoting both basal and insulin-stimulated glucose uptake. Our finding reveals also a novel role of DNAJB3 in eliciting Glut4 translocation to the plasma membrane. These results suggest a physiological role of DNAJB3 in mitigating metabolic stress and improving glucose homeostasis and could therefore represent a novel therapeutic target for type 2 diabetes.</p><h2>Other Information</h2> <p> Published in: Scientific Reports<br> License: <a href="https://creativecommons.org/licenses/by/4.0" target="_blank">https://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="http://dx.doi.org/10.1038/s41598-019-41244-8" target="_blank">http://dx.doi.org/10.1038/s41598-019-41244-8</a></p>2019-03-18T00:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1038/s41598-019-41244-8https://figshare.com/articles/journal_contribution/DNAJB3_attenuates_metabolic_stress_and_promotes_glucose_uptake_by_eliciting_Glut4_translocation/21598113CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/215981132019-03-18T00:00:00Z |
| spellingShingle | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation Abdelilah Arredouani (10914455) Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics DNAJB3 Heat Shock Response Insulin Resistance Type 2 Diabetes Obesity |
| status_str | publishedVersion |
| title | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| title_full | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| title_fullStr | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| title_full_unstemmed | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| title_short | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| title_sort | DNAJB3 attenuates metabolic stress and promotes glucose uptake by eliciting Glut4 translocation |
| topic | Biomedical and clinical sciences Clinical sciences Medical biochemistry and metabolomics DNAJB3 Heat Shock Response Insulin Resistance Type 2 Diabetes Obesity |