Streptococcus mutans regulates ubiquitin modification of Candida albicans in the bacterial-fungal interaction

The ecological interplay between Streptococcus mutans and Candida albicans within dental plaque biofilms is an important factor driving pathogenesis of dental caries. This study aimed to investigate S . mutans regulation of C . albicans growth and virulence through extracellular membrane vesicles (EMVs) and modulation of ubiquitination, a key protein post-translational modification. We established a transwell co-culture model to enable “contact-independent” interactions between S . mutans and C . albicans . S . mutans EMVs were found to directly associate with C . albicans cells and promote biofilm formation and growth. Quantitative ubiquitination profiling revealed S . mutans dramatically alters the ubiquitination landscape in C . albicans . We identified 10,661 ubiquitination sites across the C . albicans proteome and their enrichment in pathways related to translation, metabolism, and stress adaptation. Co-culture with S . mutans led to upregulation of ubiquitination on 398 proteins involved in sugar catabolism and generation of reducing power. S . mutans upregulated ubiquitination of superoxide dismutase-3 of C . albicans , inducing its degradation and heightened reactive oxygen species levels, and concomitantly stimulated C . albicans growth. Our findings elucidate EMVs and ubiquitination modulation as key mechanisms governing the S . mutans-C . albicans interplay and provide new insights into the promotion of a cariogenic oral biofilm environment. This study significantly advances understanding of the complex molecular interactions underlying dental plaque dysbiosis and caries pathogenesis.