Intracellular pools of the heterotrimeric G-protein α-subunit Gαi3 (encoded by GNAI3) have been shown to promote growth factor signaling, while at the same time inhibiting the activation of JNK and autophagic signaling following nutrient starvation. The precise molecular mechanisms linking Gαi3 to both stress and growth factor signaling remain poorly understood. Importantly, JNK-mediated phosphorylation of Bcl-2 was previously found to activate autophagic signaling following nutrient deprivation. Our data shows that activated Gαi3 decreases Bcl-2 phosphorylation, whereas inhibitors of Gαi3, such as RGS4 and AGS3 (also known as GPSM1), markedly increase the levels of phosphorylated Bcl-2. Manipulation of the palmitoylation status and intracellular localization of RGS4 suggests that Gαi3 modulates phosphorylated Bcl-2 levels and autophagic signaling from discreet TGN38 (also known as TGOLN2)-labeled vesicle pools. Consistent with an important role for these molecules in normal tissue responses to nutrient deprivation, increased Gαi signaling within nutrient-starved adrenal glands from RGS4-knockout mice resulted in a dramatic abrogation of autophagic flux, compared to wild-type tissues. Together, these data suggest that the activity of Gαi3 and RGS4 from discreet TGN38-labeled vesicle pools are critical regulators of autophagic signaling that act via their ability to modulate phosphorylation of Bcl-2.

异源三聚体 G 蛋白 α 亚基 Gαi3（由GNAI3编码）的细胞内池已被证明可以促进生长因子信号传导，同时抑制营养饥饿后 JNK 和自噬信号传导的激活。将 Gαi3 与应激和生长因子信号传导联系起来的精确分子机制仍知之甚少。重要的是，之前发现 JNK 介导的 Bcl-2 磷酸化可在营养剥夺后激活自噬信号传导。我们的数据显示，激活的 Gαi3 会降低 Bcl-2 磷酸化，而 Gαi3 抑制剂，例如 RGS4 和 AGS3（也称为 GPSM1），会显着增加磷酸化 Bcl-2 的水平。对 RGS4 棕榈酰化状态和细胞内定位的操纵表明，Gαi3 调节磷酸化 Bcl-2 水平和来自谨慎的 TGN38（也称为 TGOLN2）标记的囊泡池的自噬信号。与这些分子在正常组织对营养缺乏的反应中的重要作用相一致，与野生型组织相比，RGS4 敲除小鼠营养饥饿的肾上腺内 Gαi 信号传导的增加导致自噬通量的显着消除。总之，这些数据表明，来自谨慎的 TGN38 标记的囊泡库的 Gαi3 和 RGS4 的活性是自噬信号传导的关键调节因子，通过其调节 Bcl-2 磷酸化的能力发挥作用。