Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

Background: c-FLIP L is a regulator of caspase-8 activity in T lymphocytes. Results: Caspase-8 activity is lost upon deletion of c-FLIP L . p43FLIP rescues caspase-8 activity through Raf1, TRAF2, and RIPK1 association, augmenting ERK and NF-B pathways. Conclusion:The FLIP L cleavage product p43FLIP promotes activation of pathways involved with T cell growth. Significance: This study provides new insight into the regulation of caspase-8 activity by c-FLIP.