Human Golgi Antiapoptotic Protein Modulates Intracellular Calcium Fluxes

Abstract

Golgi antiapoptotic protein (GAAP) is a novel regulator of cell death that is highly conserved in eukaryotes and present in some poxviruses, but its molecular mechanism is unknown. Given that alterations in intracellular Ca 2؉ homeostasis play an important role in determining cell sensitivity to apoptosis, we investigated if GAAP affected Ca 2؉ signaling. Overexpression of human (h)-GAAP suppressed staurosporine-induced, capacitative Ca 2؉ influx from the extracellular space. In addition, it reduced histamine-induced Ca 2؉ release from intracellular stores through inositol trisphosphate receptors. h-GAAP not only decreased the magnitude of the histamine-induced Ca 2؉ fluxes from stores to cytosol and mitochondrial matrices, but it also reduced the induction and frequency of oscillatory changes in cytosolic Ca 2؉ . Overexpression of h-GAAP lowered the Ca 2؉ content of the intracellular stores and decreased the efficacy of IP 3 , providing possible explanations for the observed results. Opposite effects were obtained when h-GAAP was knocked down by siRNA. Thus, our data demonstrate that h-GAAP modulates intracellular Ca 2؉ fluxes induced by both physiological and apoptotic stimuli.

Deletion of the Human Cytomegalovirus US17 Gene Increases the Ratio of Genomes per Infectious Unit and Alters Regulation of Immune and Endoplasmic Reticulum Stress Response Genes at Early and Late Times after Infection

“…We note that US12 family members share sequence similarity with the transmembrane Bax inhibitor 1 (TMBIM) family of conserved eukaryotic antiapoptotic seven-transmembrane proteins (11). These proteins localize to the membranes of various cellular organelles, where they act as rheostats that modulate apoptotic and ER stress signaling by influencing cellular calcium levels (41)(42)(43)(44)(45). Taken together, it is possible that US17 is a Bax inhibitor 1 ortholog that shapes virion composition by modulating the levels of ER stress response and apoptosis genes involved in regulation of protein folding, trafficking, and cVAC function.…”

STAMP1 Is Both a Proliferative and an Antiapoptotic Factor in Prostate Cancer

“…4). It is possible that STAMP1 interacts with and affects the function of an antiapoptotic protein, for example, Golgi antiapoptotic protein, which is localized to the Golgi similar to STAMP1, which has recently been reported to inhibit apoptosis by modulating intracellular calcium fluxes (29). Furthermore, it is possible that STAMP1 is involved in endocytic trafficking of cell surface receptors and influences receptor signaling, which mediates cell growth or apoptosis.…”

Transmembrane BAX Inhibitor Motif Containing (TMBIM) Family Proteins Perturbs a trans-Golgi Network Enzyme, Gb3 Synthase, and Reduces Gb3 Biosynthesis

“…For example, FAIM2 was identified as Fas inhibitory molecule 2 (26), and BI-1 was first identified as BAX inhibitor-1 (25). BI-1 and GAAP have been reported to modulate the intracellular calcium flux, which inhibits apoptosis by several stimuli (38,39). An interesting feature of the family is their highly conserved multispanning transmembrane domains named UPF0005; however, the biological activity of the domain is still unknown.…”