ORP4L couples IP3 to ITPR1 in control of endoplasmic reticulum calcium release
ORP4L couples IP3 to ITPR1 in control of endoplasmic reticulum calcium release
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ORP4L 将 IP3 与 ITPR1 偶联来控制内质网钙释放
DOI：
10.1096/fj.201900933rr
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发表时间：
2019-12-01
期刊：
影响因子：
4.8
通讯作者：
Zhong, Wenbin
中科院分区：
文献类型：
--
作者：
Cao, Xiuye;Chen, Jianuo;Zhong, Wenbin
氧甾醇结合蛋白相关蛋白（ORP） 4L作为一种支架蛋白，将CD3-epsilon、g - α (q/11)和plc - β 3组装成质膜复合物，介导t细胞急性淋巴细胞白血病细胞中肌醇(1,4,5)-三磷酸（IP3）诱导的内质网（ER） Ca2+释放和氧化磷酸化。在这里，我们提供了新的证据，证明ORP4L与Jurkat T细胞中IP3受体1型（ITPR1）的羧基端相互作用。ORP4L使IP3与ITPR1绑定；缺少ITPR1结合区的截断结构保留了增加IP3产生的能力，但不能介导IP3和ITPR1的结合。与ORP4L的这种能力相关，它增强内质网Ca2+释放和随后的细胞质和线粒体平行Ca2+峰值振荡，刺激线粒体能量，从而维持细胞存活。这些数据支持一个新的模型，其中ORP4L是ITPR1的辅助因子，增加ITPR1对IP3的敏感性，并使ER Ca2+释放。
Oxysterol-binding protein related protein (ORP) 4L acts as a scaffold protein assembling CD3-epsilon, G-alpha(q/11), and PLC-beta 3 into a complex at the plasma membrane that mediates inositol (1,4,5)-trisphosphate (IP3) induced endoplasmic reticulum (ER) Ca2+ release and oxidative phosphorylation in T-cell acute lymphoblastic leukemia cells. Here, we offer new evidence that ORP4L interacts with the carboxyl terminus of the IP3 receptor type 1 (ITPR1) in Jurkat T cells. ORP4L enables IP3 binding to ITPR1; a truncated construct that lacks the ITPR1-binding region retains the ability to increase IP3 production but fails to mediate IP3 and ITPR1 binding. In association with this ability of ORP4L, it enhances Ca2+ release from the ER and subsequent cytosolic and mitochondrial parallel Ca2+ spike oscillations that stimulate mitochondrial energetics and thus maintains cell survival. These data support a novel model in which ORP4L is a cofactor of ITPR1, which increases ITPR1 sensitivity to IP3 and enables ER Ca2+ release.