Decoding protein persulfidation signaling

ongoing

Life originally emerged and flourished in hydrogen sulfide (H2S)-rich environment and literature published in the past decade started to recognize that H2S is a mediator of many physiological and pathological processes. Exposure to H2S can put animals into suspended animation-like state while the lifespan extensions by the dietary restriction are caused by H2S accumulation. Disturbances in its production are linked to the development of neurodegenerative diseases and cancer, among many others. A new post-translational modification (PTM) of cysteine residues called protein persulfidation (i.e., converting cysteine residues PSH to persulfides, PSSH) has been suggested as a unifying mechanism behind all these effects. Therefore, an understanding of protein persulfidation has not only a fundamental potential, e.g. unraveling new signaling pathways, but also a pharmacological potential in fighting aging and diseases. However, the underlying mechanisms of H2S-mediated PSSH formation are still unclear, mainly due to the lack of a reliable and selective methodology for PSSH labeling. Here, using cutting-edge methodology for PSSH labeling developed by our team, combined with proteomics, metabolomics and molecular biology, and by working on different model systems (cells, C. elegans, rodents) we intend to (i) gain high-resolution structural, functional, quantitative, and spatio-temporal information on PSSH dynamics and position this evolutionary conserved PTM in the global cell signalling scheme, particularly in relation to other cysteine PTMs, (ii) understand the intricate relation between aging and PSSH and (iii) identify the protein targets whose change of function by persulfidation is implicated in aging and disease progression. The ultimate objective is to pave the way for the development of innovative therapeutic strategies that will permit targeted redox control of cell metabolism, and delay aging and disease progression.