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Among the virulence factors produced by B. pertussis, pertussis toxin (PT) is responsible for key disease symptoms, including impacts on the immune system. PT is an AB5 toxin, consisting of a single catalytic A subunit and five B subunits. The B pentamer recognizes cell surface glycans and facilitates intracellular delivery of the catalytic A subunit. PT also impacts host cell signaling via mechanisms that do not depend on the catalytic activity of the A subunit. In particular, PT promotes signaling through the T-cell receptor (TCR), leading to activation of extracellular signal-regulated kinase (ERK) cascades. PT prefers to bind sialylated and N-linked glycans, but other aspects of PT\u2019s glycan binding specificity remain underexplored. Here we report that the absence of fucose on mammalian cell surfaces leads to increased binding by PT. Using pharmacological inhibitors in a human bronchial epithelial cell line, we observe that sialylation and N-linked glycosylation promote PT binding while fucosylation interferes with PT binding. Similarly, CHO and Colo205 cells deficient in fucosylation exhibited enhanced PT binding as compared to the corresponding wild-type cell lines. Genetic knockout of FUT3\/FUT5\/FUT6 or of FUT8 led to increased PT binding, suggesting that specific fucosylated epitopes mediate protection from PT. The functional impact of altered PT binding was examined in Jurkat T cells, where removal of cell surface non-core fucose led to increased PT-dependent ERK phosphorylation. In sum, our study identifies a role for fucosylation in protecting mammalian cells from PT.<\/jats:p>","DOI":"10.1093\/glycob\/cwag011","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T12:43:43Z","timestamp":1772023423000},"source":"Crossref","is-referenced-by-count":0,"title":["Hypofucosylation promotes pertussis toxin binding to cell surface glycococonjugates and pertussis toxin-induced intracellular ERK signaling"],"prefix":"10.1093","volume":"36","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3495-7068","authenticated-orcid":false,"given":"Rohit Sai Reddy","family":"Konada","sequence":"first","affiliation":[{"name":"Department of Biochemistry, 5323 Harry Hines Blvd, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5209-1958","authenticated-orcid":false,"given":"Nicole","family":"Nischan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, 5323 Harry Hines Blvd, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9758-3454","authenticated-orcid":false,"given":"Aurora","family":"Silva","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, 5323 Harry Hines Blvd, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5373-3329","authenticated-orcid":false,"given":"Jennifer J","family":"Kohler","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, 5323 Harry Hines Blvd, UT Southwestern Medical Center , Dallas, TX 75390 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"2026030900363754300_ref1","doi-asserted-by":"publisher","first-page":"L828","DOI":"10.1152\/ajplung.00120.2006","article-title":"Airway epithelial wound repair: role of carbohydrate sialyl Lewisx","volume":"291","author":"Allahverdian","year":"2006","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"2026030900363754300_ref2","doi-asserted-by":"publisher","first-page":"1167908","DOI":"10.3389\/fimmu.2023.1167908","article-title":"Acute and chronic lung inflammation drives changes in epithelial glycans","volume":"14","author":"Alvarez","year":"2023","journal-title":"Front Immunol"},{"key":"2026030900363754300_ref3","doi-asserted-by":"publisher","first-page":"5139","DOI":"10.1128\/IAI.00895-08","article-title":"Pertussis toxin inhibits early chemokine production to delay neutrophil recruitment in response to Bordetella pertussis respiratory tract infection in mice","volume":"76","author":"Andreasen","year":"2008","journal-title":"Infect Immun"},{"key":"2026030900363754300_ref4","doi-asserted-by":"publisher","first-page":"8677","DOI":"10.1016\/S0021-9258(18)68358-9","article-title":"Use of glycosyltransferases to restore pertussis toxin receptor activity to asialoagalactofetuin","volume":"263","author":"Armstrong","year":"1988","journal-title":"J Biol Chem"},{"key":"2026030900363754300_ref5","doi-asserted-by":"publisher","first-page":"41R","DOI":"10.1093\/glycob\/cwg054","article-title":"Fucose: biosynthesis and biological function in mammals","volume":"13","author":"Becker","year":"2003","journal-title":"Glycobiology."},{"key":"2026030900363754300_ref6","doi-asserted-by":"publisher","first-page":"6034","DOI":"10.1016\/j.vaccine.2009.07.074","article-title":"First report and detailed characterization of B. 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