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Peroxisome-derived hydrogen peroxide can modulate the sulfenylation profiles of key redox signaling proteins

Ever since the first characterization of peroxisomes, a central theme has been their involvement in cellular hydrogen peroxide (H2O2) metabolism. While the reputation of H2O2 drastically changed from an exclusively toxic molecule to a signaling messenger, the regulatory role of peroxisomes in these signaling events is still largely underappreciated. This is mainly because the number of known protein targets of peroxisome-derived H2O2 is rather limited and testing of specific targets is predominantly based on knowledge previously gathered in related fields of research. To gain a broader and more systematic insight into the role of peroxisomes in redox signaling, an unbiased approach is urgently needed. To accomplish this goal, we have combined a previously developed cell system in which peroxisomal H2O2 production can be modulated with a yeast AP-1-like-based sulfenome mining strategy to inventory protein thiol targets of peroxisome-derived H2O2 in different subcellular compartments. Using this unbiased approach, we were able to identify specific and common targets of peroxisome-derived and exogenous H2O2 in peroxisomes, the cytosol, and mitochondria. We also observed that the sulfenylation kinetics profiles of key targets belonging to different protein families can vary considerably. In addition, we obtained compelling but indirect evidence that peroxisome-derived H2O2 may oxidize at least some of its targets through a redox relay mechanism. In conclusion, given that sulfenic acids function as key intermediates in H2O2 signaling, the findings presented in this study provide initial but critical insight into how peroxisomes may be integrated in the cellular H2O2 signaling network. Highlights YAP1C-trapping is a robust tool to assess the peroxisomal H2O2-dependent sulfenome Exogenous and peroxisome-derived H2O2 have both common and distinct targets ANXA2, PRDX1, and SKP1 are major targets of peroxisome-derived H2O2 The sulfenylation kinetics profiles of key redox-active proteins vary considerably Production of H2O2 inside peroxisomes directly impacts the mitochondrial sulfenome