Protein persulfidation, a major post-translational modification mediated by the gaseous signaling molecule hydrogen sulfide (H₂S), regulates diverse physiological processes in eukaryotes and bacteria. However, its existence and functional roles in archaea, the third domain of life, remain entirely unexplored. Here, we investigate persulfidation in the deep-sea hyperthermophilic archaeon Thermococcus aciditolerans SY113, which thrives in sulfur rich hydrothermal vents and endogenously produces substantial H₂S. Our profiling not only delineated the unique reactivity landscape of this modification but also enabled quantitative analysis of its dynamic regulation by H₂S. A total of 204 persulfidation sites on 171 proteins were identified, of which over 65% were dynamically regulated by H₂S. Further functional analysis suggests that persulfidation represents an ancient and conserved regulatory mechanism in primordial life, including the regulation of catalytic activity and maintenance of protein conformation. Collectively, our findings provide a valuable dataset and a theoretical foundation for understanding the role of persulfidation in the physiological regulation of deep-sea hyperthermophilic archaea.
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