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Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4

Wang, HongBin and Ricklin, Daniel and Lambris, John D.. (2017) Complement-activation fragment C4a mediates effector functions by binding as untethered agonist to protease-activated receptors 1 and 4. Proceedings of the National Academy of Sciences of the United States of America, 114 (41). pp. 10948-10953.

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Official URL: http://edoc.unibas.ch/58345/

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Abstract

C4a is a small protein released from complement component C4 upon activation of the complement system's classical and lectin pathways, which are important constituents of innate immune surveillance. Despite the structural similarity between C4a and well-described anaphylatoxins C3a and C5a, the binding partner and biological function of C4a have remained elusive. Using a cell-based reporter assay, we screened C4a against a panel of both known and orphan G protein-coupled receptors and now provide evidence that C4a is a ligand for protease-activated receptor (PAR)1 and PAR4. Whereas C4a showed no activity toward known anaphylatoxin receptors, it acted as an agonist for both PAR1 and PAR4 with nanomolar activity. In human endothelial cells, ERK activation by C4a was mediated through both PAR1 and PAR4 in a Gαi-independent signaling pathway. Like other PAR1 activators, C4a induced calcium mobilization through the PAR1/Gαq/PLCβ signaling axis. Moreover, C4a increased stress fiber formation and enhanced endothelial permeability, both of which were reduced by PAR1 antagonists. In sum, our study identifies C4a as an untethered agonist for PAR1 and PAR4 with effects on cellular activation and endothelial permeability, thereby revealing another instance of cross-talk between the complement system and other host defense pathways.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molekulare Pharmazie (Ricklin)
UniBasel Contributors:Ricklin, Daniel
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:National Academy of Sciences
ISSN:0027-8424
e-ISSN:1091-6490
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:30 May 2018 08:42
Deposited On:30 May 2018 08:42

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