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MBC in Press, published online ahead of print October 29, 2008
Mol. Biol. Cell 10.1091/mbc.E08-06-0587

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Submitted on June 11, 2008
Revised on September 24, 2008
Accepted on October 22, 2008

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,{dagger}{ddagger} and Evangelia G. Kranias*{ddagger}{sect}

*Molecular Biology Division, Biomedical Research Foundation, Academy of Athens, Athens 115 27, Greece; {dagger}Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201; {sect}Department of Pharmacology and Cell Biophysics, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0575

Monitoring Editor: M. Bishr Omary

Cardiac contractility is regulated through the activity of various key Ca2+-handling proteins. The sarco(endo)plasmic reticulum (SR) Ca2+ transport ATPase (SERCA2a) and its inhibitor phospholamban (PLN) control the uptake of Ca2+ by SR membranes during relaxation. Recently, the anti-apoptotic 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 HEK 293 cells, recombinant SERCA2 was specifically targeted to the ER, while 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, following 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 Ca2+ levels. These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus ER Ca2+ stores.

{ddagger}These authors contributed equally to this work.

Address correspondence to: Evangelia G. Kranias (litsa.kranias{at}uc.edu)




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