HECT E3 Ubiquitin Ligase Nedd4 Is Required for Antifungal Innate Immunity

Candida albicans is the most common cause of fungal infections in humans, and disseminated candidiasis has become one of the leading causes of hospital-acquired bloodstream infections with a high mortality rate. However, little is known about the host-pathogen interactions and the mechanisms of antifungal immunity. Here, we report that Nedd4 (neuronal precursor cell-expressed 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(-/- )macrophages displayed impaired activation of TGF-beta-activating kinase-1 and NF-kappa B, but normal activation of spleen tyrosine kinase and protein kinase C-delta on C. albicans yeast and hyphal infections. These data suggest that Nedd4 regulates signaling events downstream of protein kinase C-delta but upstream of or at TGF-beta-activating kinase-1.

Automated summary

The study revealed the essential role of Nedd4 in signaling through Dectin-1 and Dectin-2/3, with Nedd4-deficient mice showing increased susceptibility to systemic C. albicans infection. The molecular mechanisms involve impaired activation of TGF-beta-activating kinase-1 and NF-kappa B in macrophages lacking Nedd4, highlighting the regulatory role of Nedd4 in antifungal immunity.