Pharmacoproteomics pinpoints HSP70 interaction for correction of the most frequent Wilson disease-causing mutant of ATP7B

Mafalda Concilli, Raffaella Petruzzelli, Silvia Parisi, Federico Catalano, Francesco Sirci, Francesco Napolitano, Mario Renda, Luis J. Galietta, Diego Di Bernardo, Roman S. Polishchuk

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Pathogenic mutations in the copper transporterATP7Bhave 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.
Original languageEnglish (US)
Pages (from-to)32453-32463
Number of pages11
JournalPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume117
Issue number51
DOIs
StatePublished - 2020
Externally publishedYes

ASJC Scopus subject areas

  • General

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