Journal Article
BI-1 Regulates Endoplasmic Reticulum Ca²⁺ Homeostasis Downstream of Bcl-2 Family Proteins [2008]
Xu, Chunyan; Xu, Wenjie; Palmer, Amy E.; Reed, John C.;
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BI-1 (Bax inhibitor-1) is an evolutionarily conserved multitransmembrane protein that resides in the endoplasmic reticulum (ER) and that has documented cytoprotective functions in both animals and plants. Recent studies indicate that BI-1 shares in common with Bcl-2/Bax family proteins the ability to regulate the amounts of Ca²⁺ that can be released from the ER by agents, such as the ER-Ca²⁺-ATPase (SERCA) inhibitor thapsigargin (TG). Using an ER-targeted, Ca²⁺ indicator (cameleon), with characteristics optimized for measuring ER Ca²⁺ ([Ca²⁺]er), we studied the effects of BI-1 on [Ca²⁺]er in resting and TG-treated cells. Similar to cells overexpressing antiapoptotic Bcl-2 or Bcl-XL, overexpression of BI-1 resulted in lower resting [Ca²⁺]er, with concomitantly less Ca²⁺ released into the cytosol upon stimulation by TG and with a higher rate of Ca²⁺ leakage from the ER. Co-expression of SERCA restored levels of [Ca²⁺]er to normal, showing opposing actions of the ER-Ca²⁺ATPase and BI-1 on ER Ca²⁺ homeostasis. Conversely, cells with deficient BI-1 have increased [Ca²⁺]er, and release more Ca²⁺ into the cytosol when challenged with TG. In BI-1-deficient cells, Bcl-XL fails to reduce [Ca²⁺]er, indicating that BI-1 functions downstream of Bcl-XL. In bax⁻/⁻bak⁻/⁻ double knock-out cells, both BI-1 and Bcl-XL retained their ability to reduce [Ca²⁺]er, suggesting that BI-1 and Bcl-XL operate downstream of or parallel to Bax/Bak. The findings reveal a hierarchy of fun
ctional interactions of BI-1 with Bcl-2/Bax family proteins in regulating ER Ca²⁺ homeostasis.
