Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordData and Code Availability The raw data corresponding to the antibody microarray Detection of persulfidation of EGFR Pathway kinases represent entirely new application of the dimedone switch method and are therefore available in more detail from the corresponding author on request. Proteomic data used for Figure S2C are stored in Data S1 and S2 and for Figures S3H and S3I in Data S3 and S4. All in-gel persulfidation, as well as Western blot sufenylation and sulfynilation data are reported in main and supporting Figures. Other raw data are available at https://data.mendeley.com/datasets/pw2wz39tsk/2Life on Earth emerged in a hydrogen sulfide (H2S)-rich environment eons ago and with it protein persulfidation mediated by H2S evolved as a signaling mechanism. Protein persulfidation (S-sulfhydration) is a post-translational modification of reactive cysteine residues, which modulate protein structure and/or function. Persulfides are difficult to label and study due to their reactivity and similarity with cysteine. Here, we report a facile strategy for chemoselective persulfide bioconjugation using dimedone-based probes, to achieve highly selective, rapid, and robust persulfide labeling in biological samples with broad utility. Using this method, we show persulfidation is an evolutionarily conserved modification and waves of persulfidation are employed by cells to resolve sulfenylation and prevent irreversible cysteine overoxidation preserving protein function. We report an age-associated decline in persulfidation that is conserved across evolutionary boundaries. Accordingly, dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli.IDEX BordeauxFRMMedical Research Council (MRC)Brian Ridge ScholarshipNorthcott Devon Medical Research FoundationMinistry of Education, Science and Technology Development of the Republic of SerbiaNIHDFG, GermanyAmerican Heart Association-Allen Initiative in Brain Health and Cognitive Impairmen