P2X7 receptor activation regulates rapid unconventional export of transglutaminase-2

Adamczyk, Magdalena ORCID: https://orcid.org/0000-0002-7405-5157, Griffiths, Rhiannon, Dewitt, Sharon ORCID: https://orcid.org/0000-0001-8169-8241, Knauper, Vera ORCID: https://orcid.org/0000-0002-3965-9924 and Aeschlimann, Daniel ORCID: https://orcid.org/0000-0003-0930-7706 2015. P2X7 receptor activation regulates rapid unconventional export of transglutaminase-2. Journal of Cell Science 128 (24) , pp. 4615-4628. 10.1242/jcs.175968

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Abstract

Transglutaminases (TG) are externalized from cells via an unknown unconventional secretory pathway. We show for the first time that purinergic signaling regulates active secretion of TG2, an enzyme with a pivotal role in stabilizing extracellular matrices and modulating cell-matrix interactions in tissue repair. Extracellular ATP promotes TG2 secretion by macrophages, and this can be blocked by a purinergic receptor P2X7 (P2X7R)-selective antagonist. Introduction of functional P2X7R into HEK293 cells is sufficient to confer rapid, regulated TG2 export. By employing pharmacological agents, TG2 release could be separated from P2X7R-mediated microvesicle shedding. Neither, Ca2+ signaling alone nor membrane depolarization triggered TG2 secretion which occurred only upon receptor membrane pore formation and without pannexin channel involvement. A gain-of-function mutation in P2X7R associated with autoimmune disease caused enhanced TG2 externalization from cells, and this correlated with increased pore activity. These results provide a mechanistic explanation for a link between active TG2 secretion and inflammatory responses, and aberrant enhanced TG2 activity in certain autoimmune conditions.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Dentistry
Subjects:	Q Science > Q Science (General) Q Science > QP Physiology R Medicine > RM Therapeutics. Pharmacology
Additional Information:	This is an Open Access article distributed under the terms of the Creative Commons Attribution License
Publisher:	Company of Biologists
ISSN:	0021-9533
Funders:	Arthritis Research UK, Cardiff University President's Scholarships
Related URLs:	http://jcs.biologists.org/
Date of First Compliant Deposit:	30 March 2016
Date of Acceptance:	29 October 2015
Last Modified:	11 Oct 2023 18:22
URI:	https://orca.cardiff.ac.uk/id/eprint/80885

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