Triglycerides induce endoplasmic reticulum lipid bilayer stress to activate PERK and enhance antifungal immunity.

Invasive fungal infections remain a major clinical challenge due to limited antifungal drugs, drug toxicity, and resistance. Fungal infections trigger endoplasmic reticulum (ER) stress. However, the mechanism through which this stress response affects antifungal immunity remains unclear. Here, we showed that de novo triglyceride synthesis promotes antifungal innate immune signaling and proinflammatory gene expression in macrophages. Upon fungal stimulation, triglycerides induce ER lipid bilayer stress and activate the protein kinase R (PKR)-like ER kinase (PERK) branch of the unfolded protein response pathway. Furthermore, activated PERK mediates autophagic degradation of Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1) to amplify spleen tyrosine kinase-associated antifungal signaling. Mice with PERK deficiency in myeloid cells are more susceptible to the lethal sequelae of systemic infection with Candida albicans. Notably, administration of the PERK agonist CCT020312 improved host outcomes in disseminated fungal infections. Overall, our study identified a critical function of PERK in positively regulating antifungal immune responses and offers a potential therapeutic strategy for controlling C. albicans infections.