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Sluysmans S, Méan I, Xiao T, et al. PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis. Mol Biol Cell. 2021;32(21):ar34doi: 10.1091/mbc.E21-07-0355.
Sluysmans, S., Méan, I., Xiao, T., Boukhatemi, A., Ferreira, F., Jond, L., Mutero, A., Chang, C. J., & Citi, S. (2021). PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis. Molecular biology of the cell, 32(21), ar34. https://doi.org/10.1091/mbc.E21-07-0355
Sluysmans, Sophie, et al. "PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis." Molecular biology of the cell vol. 32,21 (2021): ar34. doi: https://doi.org/10.1091/mbc.E21-07-0355
Sluysmans S, Méan I, Xiao T, Boukhatemi A, Ferreira F, Jond L, Mutero A, Chang CJ, Citi S. PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis. Mol Biol Cell. 2021 Nov 01;32(21):ar34. doi: 10.1091/mbc.E21-07-0355. Epub 2021 Oct 06. PMID: 34613798.
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Mol Biol Cell. 2021 Nov 01;32(21):ar34. doi: 10.1091/mbc.E21-07-0355. Epub 2021 Oct 06.

PLEKHA5, PLEKHA6, and PLEKHA7 bind to PDZD11 to target the Menkes ATPase ATP7A to the cell periphery and regulate copper homeostasis.

Molecular biology of the cell

Sophie Sluysmans, Isabelle Méan, Tong Xiao, Amina Boukhatemi, Flavio Ferreira, Lionel Jond, Annick Mutero, Christopher J Chang, Sandra Citi

Affiliations

  1. Department of Cell Biology, Faculty of Sciences, University of Geneva, CH-1205 Geneva, Switzerland.
  2. Department of Chemistry, University of California, Berkeley, Berkeley, CA 94720.
  3. Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720.

PMID: 34613798 DOI: 10.1091/mbc.E21-07-0355

Abstract

Copper homeostasis is crucial for cellular physiology and development, and its dysregulation leads to disease. The Menkes ATPase ATP7A plays a key role in copper efflux, by trafficking from the Golgi to the plasma membrane upon cell exposure to elevated copper, but the mechanisms that target ATP7A to the cell periphery are poorly understood. PDZD11 interacts with the C-terminus of ATP7A, which contains sequences involved in ATP7A trafficking, but the role of PDZD11 in ATP7A localization is unknown. Here we identify PLEKHA5 and PLEKHA6 as new interactors of PDZD11 that bind to the PDZD11 N-terminus through their WW domains similarly to the junctional protein PLEKHA7. Using CRISPR-KO kidney epithelial cells, we show by immunofluorescence microscopy that WW-PLEKHAs (PLEKHA5, PLEKHA6, PLEKHA7) recruit PDZD11 to distinct plasma membrane localizations and that they are required for the efficient anterograde targeting of ATP7A to the cell periphery in elevated copper conditions. Pull-down experiments show that WW-PLEKHAs promote PDZD11 interaction with the C-terminus of ATP7A. However, WW-PLEKHAs and PDZD11 are not necessary for ATP7A Golgi localization in basal copper, ATP7A copper-induced exit from the Golgi, and ATP7A retrograde trafficking to the Golgi. Finally, measuring bioavailable and total cellular copper, metallothionein-1 expression, and cell viability shows that WW-PLEKHAs and PDZD11 are required for maintaining low intracellular copper levels when cells are exposed to elevated copper. These data indicate that WW-PLEKHAs-PDZD11 complexes regulate the localization and function of ATP7A to promote copper extrusion in elevated copper.

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