Phosphorylation of BCL-2 regulates ER Ca2+ homeostasis and apoptosis

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Abstract
Phosphorylation of BCL‐2 within an unstructured loop inhibits its antiapoptotic effect. We found that phosphorylated BCL‐2 predominantly localized to the endoplasmic reticulum (ER) and tested whether phosphorylation would control its activity at this organelle, where Ca2+ dynamics serve as a critical control point for apoptosis. Phosphorylation greatly inhibits the ability of BCL‐2 to lower [Ca2+]er and protect against Ca2+‐dependent death stimuli. Cells expressing nonphosphorylatable BCL‐2AAA exhibited increased leak of Ca2+ from the ER and further diminished steady‐state [Ca2+]er stores when compared to cells expressing BCL‐2wt. Consequently, when BCL‐2 is phosphorylated, Ca2+ discharge from the ER is increased, with a secondary increase in mitochondrial Ca2+ uptake. We also demonstrate that phosphorylation of BCL‐2 inhibits its binding to proapoptotic family members. This inhibitory mechanism manifested at the ER, where phosphorylated BCL‐2 was unable to bind proapoptotic members. [Ca2+]er proved coordinate with the capacity of BCL‐2 to bind proapoptotic BH3‐only members, further integrating the apoptotic pathway and Ca2+ modulation. Unexpectedly, the regulation of ER Ca2+ dynamics is a principal avenue whereby BCL‐2 phosphorylation alters susceptibility to apoptosis.