Infection-Induced Dynamin-2 Repurposing Drives Podosome Maturation and Mechanical Immunity

Abstract

Macrophages are the vanguard of innate immunity, relying on phagocytosis to clear invading pathogens. Podosomes in macrophages have recently emerged as mechanical structures that assemble at phagocytic cups to facilitate pathogen clearance. However, how these unique actin structures are regulated to execute antimicrobial functions remains poorly understood. Here, we reveal that fungal infection drives podosome maturation to strengthen macrophage mechanical immunity. Exposure to the opportunistic fungus Candida albicans upregulates the scaffold protein Tks5 and activates Src kinase, which repurposes dynamin-2 from a membrane fission enzyme into an actin-bundling protein. This functional switch stabilizes the podosome actin core, enhancing the adhesion and mechanical force generation required to efficiently engulf, fold, and trap invading fungi. Ultimately, our findings define a mechanobiological paradigm in which infection-induced molecular repurposing drives macrophage antifungal immunity.