Hax-1: a regulator of calcium signaling and apoptosis progression with multiple roles in human disease

Hax-1, the hematopoietic cell-specific protein-associated protein X-1, is an inhibitor of apoptosis, which has been implicated in severe congenital neutropenia (SCN), neurological disorders and cancer. Hax-1 over-expression, as found in numerous types of cancer, results in resistance to granzyme B and caspase-3 and stabilizes the X-linked inhibitor of apoptosis, whereas its absence or knockdown promotes apoptosis. Hax-1 is bound to the cytosolic faces of mitochondria and the endoplasmic reticulum (ER). Interestingly, numerous viral proteins, including the classical swine fever virus N-terminal protease (N(pro)) and human immunodeficiency virus Vpr, interact with Hax-1 and disrupt its normal localization pattern. Recent findings have demonstrated that the localization to the ER allows Hax-1 to modulate calcium signaling via interactions with polycystin-2 and sarco(endo)plasmic reticulum calcium transport ATPase 2 (SERCA2).

This review discusses how the interaction of Hax-1 with calcium-handling proteins could dominate over its other roles in apoptosis, since Hax-1 no longer blocks apoptosis on over-expression of SERCA2.

To facilitate pharmacological interference with the apoptosis-regulating functions of this protein, a better understanding of the Hax-1 intracellular targeting and protein-protein interactions is needed. Such an improved understanding would allow the generation of small molecule inhibitors that interfere with apoptosis-modulating functions of Hax-1 as seen in SCN.