The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates Its protein levels to promote cell survival

Elizabeth Vafiadaki, Demetrios A. Arvanitis, Stamatis N. Pagakis, Vasiliki Papalouka, Despina Sanoudou, Aikaterini Kontrogianni-Konstantopoulos, Evangelia G. Kranias

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    Abstract

    Cardiac contractility is regulated through the activity of various key Ca 2+-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca 2+ transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca 2+ by SR membranes during relaxation. Recently, the antiapoptotic HS-1-associated protein X-1 (HAX-1) was identified as a binding partner of PLN, and this interaction was postulated to regulate cell apoptosis. In the current study, we determined that HAX-1 can also bind to SERCA2. Deletion mapping analysis demonstrated that amino acid residues 575-594 of SERCA2's nucleotide binding domain are required for its interaction with the C-terminal domain of HAX-1, containing amino acids 203-245. In transiently cotransfected human embryonic kidney 293 cells, recombinant SERCA2 was specifically targeted to the ER, whereas HAX-1 selectively concentrated at mitochondria. On triple transfections with PLN, however, HAX-1 massively translocated to the ER membranes, where it codistributed with PLN and SERCA2. Overexpression of SERCA2 abrogated the protective effects of HAX-1 on cell survival, after hypoxia/reoxygenation or thapsigargin treatment. Importantly, HAX-1 overexpression was associated with down-regulation of SERCA2 expression levels, resulting in significant reduction of apparent ER Ca 2+ levels. These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca 2+ stores.

    Original languageEnglish
    Pages (from-to)306-318
    Number of pages13
    JournalMolecular Biology of the Cell
    Volume20
    Issue number1
    DOIs
    Publication statusPublished - 1 Jan 2009

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    ASJC Scopus subject areas

    • Molecular Biology
    • Cell Biology

    Cite this

    Vafiadaki, E., Arvanitis, D. A., Pagakis, S. N., Papalouka, V., Sanoudou, D., Kontrogianni-Konstantopoulos, A., & Kranias, E. G. (2009). The anti-apoptotic protein HAX-1 interacts with SERCA2 and regulates Its protein levels to promote cell survival. Molecular Biology of the Cell, 20(1), 306-318. https://doi.org/10.1091/mbc.E08-06-0587