The persulfidome of alveolar epithelial cells reveals persulfidation of calprotectin as critical to preserve its antifungal activity.

Persulfidation is a post-translational modification involving the specific conversion of thiols (-SH) to persulfide groups (-SSH) on cysteine residues in target proteins. This modification plays critical roles in numerous physiological and cellular processes. Previously, we demonstrated that host cell persulfidation levels influence the effectiveness of antifungal immunity against the fungal pathogen Aspergillus fumigatus. In this study, we sought to further elucidate the relationship between persulfidation and the immune response. To this end, we defined the persulfidated proteins (the persulfidome) in alveolar epithelial cells that were challenged with A. fumigatus and/or exposed to a sulfide donor, which increases cellular persulfidation. Our findings suggest that persulfidation indirectly modulates immunity through changes in RNA metabolism and translation. Additionally, calprotectin was persulfidated in response to A. fumigatus exposure, and this modification is essential for maintaining its immune-related function under oxidative stress. Our results suggest that persulfidation positively influences generalized and specific immune responses.