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However, little is known about the host\u2013pathogen interactions and the mechanisms of antifungal immunity. Here, we report that Nedd4 (neuronal precursor cell\u2013expressed developmentally downregulated 4) is essential for signaling through Dectin-1 and Dectin-2\/3. We showed that mice that lack Nedd4 globally or only in the myeloid compartment are highly susceptible to systemic C. albicans infection, which correlates with heightened organ fungal burden, defective inflammatory response, impaired leukocyte recruitment to the kidneys, and defective reactive oxygen species expression by granulocytes. At the molecular level, Nedd4\u2212\/\u2212 macrophages displayed impaired activation of TGF-\u03b2\u2013activating kinase-1 and NF-\u03baB, but normal activation of spleen tyrosine kinase and protein kinase C-\u03b4 on C. albicans yeast and hyphal infections. These data suggest that Nedd4 regulates signaling events downstream of protein kinase C-\u03b4 but upstream of or at TGF-\u03b2\u2013activating kinase-1.<\/jats:p>","DOI":"10.4049\/jimmunol.2100083","type":"journal-article","created":{"date-parts":[[2021,7,19]],"date-time":"2021-07-19T20:05:19Z","timestamp":1626725119000},"page":"868-877","source":"Crossref","is-referenced-by-count":5,"title":["HECT E3 Ubiquitin Ligase Nedd4 Is Required for Antifungal Innate Immunity"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2811-1533","authenticated-orcid":false,"given":"Patrick K","family":"Nuro-Gyina","sequence":"first","affiliation":[{"name":"Biomedical Science Graduate Program, Ohio State University , Columbus, OH"},{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Na","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengkai","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiuming","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6147-6991","authenticated-orcid":false,"given":"Thomas J","family":"Waldschmidt","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9523-5296","authenticated-orcid":false,"given":"Jian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Biomedical Science Graduate Program, Ohio State University , Columbus, OH"},{"name":"Department of Pathology, University of Iowa , Iowa City, IA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,8,1]]},"reference":[{"key":"2025022610275113700_r1","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1111\/j.1439-0507.2008.01606.x","article-title":"Epidemiological trends in skin mycoses worldwide","volume":"51","author":"Havlickova","year":"2008","journal-title":"Mycoses"},{"key":"2025022610275113700_r2","doi-asserted-by":"crossref","first-page":"165rv13","DOI":"10.1126\/scitranslmed.3004404","article-title":"Hidden killers: human fungal infections","volume":"4","author":"Brown","year":"2012","journal-title":"Sci. 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