{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T07:41:36Z","timestamp":1765438896121,"version":"3.37.3"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AI138495"],"award-info":[{"award-number":["1R01AI138495"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AI164710"],"award-info":[{"award-number":["1R01AI164710"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["R56AI139658"],"award-info":[{"award-number":["R56AI139658"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["UL1TR002649"],"award-info":[{"award-number":["UL1TR002649"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>IgE-mediated mast cell activation is a driving force in allergic disease in need of novel interventions. Statins, long used to lower serum cholesterol, have been shown in multiple large-cohort studies to reduce asthma severity. We previously found that statins inhibit IgE-induced mast cell function, but these effects varied widely among mouse strains and human donors, likely due to the upregulation of the statin target, 3-hydroxy-3-methylgutaryl-CoA reductase. Statin inhibition of mast cell function appeared to be mediated not by cholesterol reduction but by suppressing protein isoprenylation events that use cholesterol pathway intermediates. Therefore, we sought to circumvent statin resistance by targeting isoprenylation. Using genetic depletion of the isoprenylation enzymes farnesyltransferase and geranylgeranyl transferase 1 or their substrate K-Ras, we show a significant reduction in Fc\u03b5RI-mediated degranulation and cytokine production. Furthermore, similar effects were observed with pharmacological inhibition with the dual farnesyltransferase and geranylgeranyl transferase 1 inhibitor FGTI-2734. Our data indicate that both transferases must be inhibited to reduce mast cell function and that K-Ras is a critical isoprenylation target. Importantly, FGTI-2734 was effective in vivo, suppressing mast cell\u2013dependent anaphylaxis, allergic pulmonary inflammation, and airway hyperresponsiveness. Collectively, these findings suggest that K-Ras is among the isoprenylation substrates critical for Fc\u03b5RI-induced mast cell function and reveal isoprenylation as a new means of targeting allergic disease.<\/jats:p>","DOI":"10.4049\/jimmunol.2200862","type":"journal-article","created":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T13:40:50Z","timestamp":1689342050000},"page":"527-538","source":"Crossref","is-referenced-by-count":4,"title":["Inhibiting Isoprenylation Suppresses Fc\u03b5RI-Mediated Mast Cell Function and Allergic Inflammation"],"prefix":"10.1093","volume":"211","author":[{"given":"Jordan M","family":"Dailey","sequence":"first","affiliation":[{"name":"Department of Microbiology and Immunology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sydney A","family":"Kee","sequence":"additional","affiliation":[{"name":"Department of Biology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuj","family":"Tharakan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aslamuzzaman","family":"Kazi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, and Massey Cancer Center, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jason R","family":"Burchett","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3138-0037","authenticated-orcid":false,"given":"Elizabeth Motunrayo","family":"Kolawole","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Utah , Salt Lake City, UT"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Boyd Ballance","sequence":"additional","affiliation":[{"name":"Department of Biology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aditya","family":"Kotha","sequence":"additional","affiliation":[{"name":"Department of Biology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1768-6654","authenticated-orcid":false,"given":"Quang T","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4379-6729","authenticated-orcid":false,"given":"Lawrence B","family":"Schwartz","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1989-8255","authenticated-orcid":false,"given":"David B","family":"Straus","sequence":"additional","affiliation":[{"name":"Department of Biology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9948-5463","authenticated-orcid":false,"given":"Rebecca K","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Said M","family":"Sebti","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, and Massey Cancer Center, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John J","family":"Ryan","sequence":"additional","affiliation":[{"name":"Department of Biology, Virginia Commonwealth University , Richmond, VA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"2025020406064945100_r1","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/S0952-7915(99)80010-7","article-title":"Mast cells as sentinels of innate immunity","volume":"11","author":"Galli","year":"1999","journal-title":"Curr. 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