HAX-1

HAX-1 was originally identified to interact with HS1, a protein with proposed involvement in B cell signal transduction in hemopoietic cells. Recently, we identified HAX-1 as a PLN-binding partner. The minimal binding region of HAX-1 was mapped to a C-terminal fragment, encoding amino acids 203-245, whereas the PLN-binding region contained amino acids 16-22, a region that includes both the Ser16 and Thr17 phosphorylation sites. Thus, binding of HAX-1 to this region of PLN may represent a regulatory mechanism and could provide the means for controlling the conformation and activity of PLN. Similarly to the SERCA2/PLN interaction, binding of HAX-1 to PLN was found to be diminished upon phosphorylation of PLN by cAMP-dependent protein kinase and increasing Ca2+ concentrations, thus indicating that HAX-1 may regulate the functional properties of PLN in the heart. Through this association, HAX-1 could therefore have an important role on SR Ca2+ cycling (Fig.1).

Fig. 1 HAX-1 is a promising new link between Ca2+ cycling and cell survival. During cardiac contraction, part of the SR Ca2+ content that is released from RyR channels can be taken up by closely positioned mitochondria. Sequestration of Ca2+ to the SR by SERCA2a results in refilling of the SR. PLN exerts inhibitory effects on SERCA2a activity and thus represents a critical regulator of SR Ca2+ homeostasis. The anti-apoptotic protein HAX-1 interacts with PLN, an association directly implicating HAX-1 in the regulation of SR Ca2+ uptake to promote cell survival. If SR Ca2+ uptake is tightly regulated, then SR Ca2+ content is maintained at optimal levels, and subsequently, mitochondria take up optimal amounts of Ca2+ (thin arrows). This can positively regulate mitochondrial bioenergetics to support cell function and promote cell survival. Conversely, deregulation of SR Ca2+ uptake, as seen in heart failure, can affect the amount of SR Ca2+ available for release and subsequently cause mitochondrial Ca2+ overload (thick arrows). This would result in caspase activation, initiation of the apoptotic signaling cascade, and cell death. HAX-1 is emerging as a critical player in the regulation of SR Ca2+ homeostasis, with direct effects on SR Ca2+ content and cell survival.