Allosteric activation of mPR3 by GPR97 triggers PAR2 activation in neutrophils by unmasking novel tethered agonist peptides

Allosteric activation of mPR3 by GPR97 triggers PAR2 activation in neutrophils by unmasking novel tethered agonist peptides | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article Allosteric activation of mPR3 by GPR97 triggers PAR2 activation in neutrophils by unmasking novel tethered agonist peptides Hsi-Hsien Lin, Tai-Ying Chu, Kuan-Yu I, Ying-Wen Chen, Yu-Chi Chang, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8720604/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract A unique multi-receptor complex comprising GPR97, CD177, CD16b, and PAR2 was recently identified as a positive modulator of human neutrophil activation. GPR97, an adhesion G protein-coupled receptor (adhesion GPCR), binds to membrane-bound CD177-associated proteinase 3 (mPR3) and enhances its enzymatic activity. The GPR97-stimulated mPR3 then cleaves and activates PAR2, another GPCR, leading to robust inflammatory responses. However, the underlying GPR97-mediated PAR2 transactivation mechanism and its downstream signaling pathways remain poorly understood. Herein, we demonstrate that PAR2 is a unique lipid raft-dependent substrate of GPR97-activated mPR3. We further identify specific mPR3 cleavage sites on PAR2 and uncover novel intramolecular agonist peptides responsible for PAR2 activation. Lastly, we delineate the downstream signaling networks elicited by these peptide agonists, highlighting the roles of distinct G proteins and signaling effectors in shaping inflammatory responses. Collectively, our findings unveil a novel GPR97-mediated PAR2 transactivation mechanism that contributes to neutrophil activation. Biological sciences/Immunology/Innate immune cells/Granulocytes/Neutrophils Biological sciences/Immunology/Signal transduction adhesion GPCR agonistic peptide GPR97 neutrophil PAR2 proteinase 3 signaling Full Text Additional Declarations There is NO Competing Interest. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information

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