{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T11:04:49Z","timestamp":1785236689203,"version":"3.55.0"},"reference-count":110,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2024,10,11]],"date-time":"2024-10-11T00:00:00Z","timestamp":1728604800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Deutsche Forschungsgemeinschaft DFG","award":["BA-3769\/3"],"award-info":[{"award-number":["BA-3769\/3"]}]},{"name":"Deutsche Forschungsgemeinschaft DFG","award":["BA-3769\/4"],"award-info":[{"award-number":["BA-3769\/4"]}]},{"name":"CSC and Charit\u00e9 Universit\u00e4tsmedizin Berlin","award":["BA-3769\/3"],"award-info":[{"award-number":["BA-3769\/3"]}]},{"name":"CSC and Charit\u00e9 Universit\u00e4tsmedizin Berlin","award":["BA-3769\/4"],"award-info":[{"award-number":["BA-3769\/4"]}]},{"name":"ECARF (European Center for Allergy Research Foundation)","award":["BA-3769\/3"],"award-info":[{"award-number":["BA-3769\/3"]}]},{"name":"ECARF (European Center for Allergy Research Foundation)","award":["BA-3769\/4"],"award-info":[{"award-number":["BA-3769\/4"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Skin mast cells (MCs) mediate acute allergic reactions in the cutaneous environment and contribute to chronic dermatoses, including urticaria, and atopic or contact dermatitis. The cAMP response element binding protein (CREB), an evolutionarily well conserved transcription factor (TF) with over 4,000 binding sites in the genome, was recently found to form a feedforward loop with KIT, maintaining MC survival. The most selective MC function is degranulation with its acute release of prestored mediators. Herein, we asked whether CREB contributes to the expression and function of the degranulation-competent receptors Fc\u03b5RI and MRGPRX2. Interference with CREB by pharmacological inhibition (CREBi, 666-15) or RNA interference only slightly affected the expression of these receptors, while KIT was strongly attenuated. Interestingly, MRGPRX2 surface expression moderately increased following CREB-knockdown, whereas MRGPRX2-dependent exocytosis simultaneously decreased. Fc\u03b5RI expression and function were regulated consistently, although the effect was stronger at the functional level. Preformed MC mediators (tryptase, histamine, \u03b2-hexosaminidase) remained comparable following CREB attenuation, suggesting that granule synthesis did not rely on CREB function. Collectively, in contrast to KIT, Fc\u03b5RI and MRGPRX2 moderately depend on unperturbed CREB function. Nevertheless, CREB is required to maintain MC releasability irrespective of stimulus, insinuating that CREB may operate by safeguarding the degranulation machinery. To our knowledge, CREB is the first factor identified to regulate MRGPRX2 expression and function in opposite direction. Overall, the ancient TF is an indispensable component of skin MCs, orchestrating not only survival and proliferation but also their secretory competence.<\/jats:p>","DOI":"10.3390\/cells13201681","type":"journal-article","created":{"date-parts":[[2024,10,14]],"date-time":"2024-10-14T05:47:58Z","timestamp":1728884878000},"page":"1681","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["CREB Is Critically Implicated in Skin Mast Cell Degranulation Elicited via Fc\u03b5RI and MRGPRX2"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1523-6871","authenticated-orcid":false,"given":"Zhuoran","family":"Li","sequence":"first","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean","family":"Schneikert","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiva Raj","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-5278-5649","authenticated-orcid":false,"given":"Manqiu","family":"Jin","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0868-4059","authenticated-orcid":false,"given":"G\u00fcrkan","family":"Bal","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1466-8875","authenticated-orcid":false,"given":"Torsten","family":"Zuberbier","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4500-7615","authenticated-orcid":false,"given":"Magda","family":"Babina","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology IA, 12203 Berlin, Germany"},{"name":"Institute of Allergology, Charit\u00e9\u2014Universit\u00e4tsmedizin Berlin, Freie Universit\u00e4t Berlin and Humboldt Universit\u00e4t zu Berlin, Hindenburgdamm 30, 12203 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,10,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.jaci.2009.08.035","article-title":"Mechanisms of mast cell signaling in anaphylaxis","volume":"124","author":"Metcalfe","year":"2009","journal-title":"J. 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