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Title: Biomarkers for arthritis : regulation of extracellular transglutaminase activity by non-conventional export
Author: Adamczyk, Magdalena
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2013
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Transglutaminase 2 (TG2) is an enzyme with a predominant role in cell stress response and tissue repair. Dramatically increased production of this enzyme is associated with early changes in arthritis, and the activity of the protein has been shown to directly contribute to both inflammatory and degenerative arthritis, although through distinct molecular mechanisms. Aberrant TG2 activity during joint disease might lead to protein modifications that are not normally present in extracellular matrix components. Those novel epitopes can possibly serve as a qualitative biomarker besides their potential role in disease pathogenesis. TG2 is released from cells via a non-conventional route, and this mechanism controls its extracellular activity. This pathway is likely to be shared with other proteins undergoing alternative secretion, many of which are potent biological signaling molecules. The aim of this project is to investigate whether non-classical secretion of TG2 is mediated by activation of the ligand-gated ion channel 7 (P2X7R) in analogy to interleukin-1β processing and release. Specifically, we are exploring whether ATP, a P2X7R agonist, which might be released from damaged cells at the sites of injury, triggers active release of TG2 from cells. To test this hypothesis we first employed macrophage and breast cancer cell models, where P2X7R is endogenously expressed, to look for involvement of ATP signaling in TG2 externalization through microvesicle shedding. By establishing HEK293 cells stably expressing P2X7R we show for the first time that introduction of functional P2X7R alone is sufficient to reconstitute rapid non-conventional TG2 export in a cell model. P2X7R activation induced time-dependent release of TG2 but not other cytoplasmic proteins, and this response was blocked by a selective P2X7R inhibitor. TG2 release was dependent on Ca2+ influx triggered by P2X7R activation and might be related to P2X7R-dependent membrane pore formation. These results provide a mechanistic explanation for a link between active TG2 release and inflammatory responses.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Q Science (General)