Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B
Galietta, Luis J., V
Di Bernardo, Diego
Polishchuk, Roman S.
Permanent link to this recordhttp://hdl.handle.net/10754/670173
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Abstract<jats:p>Pathogenic mutations in the copper transporter<jats:italic>ATP7B</jats:italic>have been hypothesized to affect its protein interaction landscape contributing to loss of function and, thereby, to hepatic copper toxicosis in Wilson disease. Although targeting mutant interactomes was proposed as a therapeutic strategy, druggable interactors for rescue of ATP7B mutants remain elusive. Using proteomics, we found that the frequent H1069Q substitution promotes ATP7B interaction with HSP70, thus accelerating endoplasmic reticulum (ER) degradation of the mutant protein and consequent copper accumulation in hepatic cells. This prompted us to use an HSP70 inhibitor as bait in a bioinformatics search for structurally similar Food and Drug Administration-approved drugs. Among the hits, domperidone emerged as an effective corrector that recovered trafficking and function of ATP7B-H1069Q by impairing its exposure to the HSP70 proteostatic network. Our findings suggest that HSP70-mediated degradation can be safely targeted with domperidone to rescue ER-retained ATP7B mutants and, hence, to counter the onset of Wilson disease.</jats:p>
CitationConcilli, M., Petruzzelli, R., Parisi, S., Catalano, F., Sirci, F., Napolitano, F., … Polishchuk, R. S. (2020). Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B. Proceedings of the National Academy of Sciences, 117(51), 32453–32463. doi:10.1073/pnas.2006648117
SponsorsWe thank Cathal Wilson for critical reading of the manuscript and acknowledge support from Telethon Institute of Genetics and Medicine bioinformatics and microscopy cores. This work was funded by Telethon, Italy, Grant TIGEM-CBDM9 (to R.S.P.); Consiglio Nazionale delle Ricerche/Russian Foundation for Basic Research Collaboration Program, Italy- Russia Grant 18-515-7811; PRIN-2017 (2017CH4RNP) (to S.P.); the Wilson Disease Association; Associazione Nazionale Malattia di Wilson; and a Veronesi Foundation Fellowship (to R.P.).