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Furini, G. 
ORCID: 0000-0001-7206-7720, Burhan, I., Huang, L., Savoca, M.P. ORCID: 0000-0002-6465-341X, Atobatele, A. ORCID: 0000-0002-9182-6742, Johnson, T. and Verderio, E. ORCID: 0000-0001-9153-8997,
2020.
Insights on the heparan sulphate-dependent externalisation of transglutaminase-2 (TG2) in glucose-stimulated proximal-like tubular epithelial cells.
Analytical Biochemistry.
ISSN 0003-2697
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1312273_Verderio.pdf - Post-print Download (1MB) | Preview |
Abstract
The extracellular matrix crosslinking enzyme transglutaminase 2 (TG2) is highly implicated in tissue fibrosis that precedes end-stage kidney failure. TG2 is unconventionally secreted through extracellular vesicles in a way that depends on heparan sulphate (HS) proteoglycan syndecan-4 (Sdc4), the deletion of which reduces experimental kidney fibrosis as a result of lower extracellular TG2 in the tubule-interstitium. Here we establish a model of TG2 externalisation in NRK-52E tubular epithelial cells subjected to glucose stress. HS-binding TG2 mutants had reduced extracellular TG2 in transfected NRK-52E, suggesting that TG2-externalisation depends on an intact TG2 heparin binding site. Inhibition of N-ethylmaleimide sensitive factor (NSF) vesicle-fusing ATPase, which was identified in the recently elucidated TG2 kidney membrane-interactome, led to significantly lower TG2-externalisation, thus validating the involvement of membrane fusion in TG2 secretion. As cyclin-G-associated kinase (GAK) had emerged as a further TG2-partner in the fibrotic kidney, we investigated whether glucose-induced TG2-externalisation was accompanied by TG2 phosphorylation in consensus sequences of cyclin-dependent kinase (CDK). Glucose stress led to intense TG2 phosphorylation in serine/threonine CDK-target. TG2 phosphorylation by tyrosine kinases was also increased by glucose. Although the precise role of glucose-induced TG2 phosphorylation is unknown, these novel data suggest that phosphorylation may be involved in TG2 membrane-trafficking.
| Item Type: | Journal article | ||||||||
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| Publication Title: | Analytical Biochemistry | ||||||||
| Creators: | Furini, G., Burhan, I., Huang, L., Savoca, M.P., Atobatele, A., Johnson, T. and Verderio, E. | ||||||||
| Publisher: | Elsevier | ||||||||
| Date: | 16 February 2020 | ||||||||
| ISSN: | 0003-2697 | ||||||||
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| Divisions: | Schools > School of Science and Technology | ||||||||
| Record created by: | Linda Sullivan | ||||||||
| Date Added: | 30 Mar 2020 11:18 | ||||||||
| Last Modified: | 31 May 2021 15:06 | ||||||||
| URI: | https://irep.ntu.ac.uk/id/eprint/39511 |
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