Jutta Diessl, Joseph Roman, Roshan Kumar, David A Hanna, Aaron Sue, Andrew Crawford, Romika Shokohi, Anya Parikh, Ajith Pattammattel, Andrew Kiss, Kewei Zhao, Ajay Larkin, Yibo Fu, Alex Guo, Timothy Durham, Maciek R Antoniewicz, Si Chen, Vishal Gohil, Vamsi Mootha, Yatrik Shah, Amit R Reddi, Kaushik Ragunathan, Ritimukta Sarangi, Thomas V O'Halloran, Martina Ralle, Ruma Banerjee
The reactivity of copper, an essential micronutrient that undergoes facile cycling between Cu 1+ and Cu 2+ redox states, is carefully controlled within the confines of protein binding sites, and by sequestration in storage vesicles, or harnessed to kill pathogens by active pumping of Cu 1+ into phagosomes. We have discovered that hydrogen sulfide, a signaling metabolite generated in copious quantities at the host-microbiome interface, upregulates Cu accumulation in diffusely dispersed puncta across the cell, as visualized by X-ray fluorescence microscopy. The Cu is predominantly in the Cu 2+ state with oxygen/nitrogen ligands. Cu import occurs via the non- canonical ZNT1 transporter, while export, following sulfide withdrawal, is ATP7A-dependent. Cu accumulates at the apices of colon crypts in a mouse model of elevated sulfide exposure due to SQOR deficiency in the intestinal epithelium, establishing in vivo relevance. Our study reveals that sulfide is a dynamic regulator of the Cu pool, stimulating Cu 2+ influx into highly concentrated puncta.