Global translational reprogramming in Trichophyton mentagrophytes-infected keratinocytes

Dermatophytosis afflicts approximately 25% of the global population, representing a critical public health burden. Trichophyton mentagrophytes (T. mentagrophytes), a predominant zoonotic dermatophyte, is a significant contributor to disease morbidity. While the transcriptomic response of keratinocytes-the primary barrier of the skin-to T. mentagrophytes infection is well characterized, the genome-wide translational regulatory mechanisms remain unknown. Here, we employed parallel ribosome profiling (Ribo-seq) and RNA sequencing (RNA-seq) to dissect the genome-wide transcriptional and translational landscape of human keratinocytes during T. mentagrophytes infection. Our analysis revealed extensive but distinct reprogramming at both transcriptional (3,189 differentially expressed genes) and translational (295 differentially translated genes) levels, with only minimal overlap (5.8% of upregulated genes and 0.8% of the downregulated genes), indicating prevalent post-transcriptional control. We further identified and characterized a vast non-canonical translatome, including 17,564 upstream ORFs (uORFs), 188,357 downstream ORFs (dORFs), and 185,704 lncRNA-derived ORFs (lncORFs). Strikingly, both translatable uORFs and dORFs were associated with significantly enhanced translation efficiency (TE) of their host genes, a phenomenon conserved under infection. Moreover, we demonstrated that miRNAs coordinately repress target gene expression at both transcriptional and translational levels. Functional interactions revealed that the presence of translated uORFs or dORFs could significantly attenuate miRNA-mediated TE suppression. This study provides the first comprehensive map of the keratinocyte translatome during fungal infection, establishing uORFs and dORFs as critical dual-layer regulators in the host anti-fungal defense.