ORP4L couples IP₃ to ITPR1 in control of endoplasmic reticulum calcium release

Oxysterol-binding protein-related protein (ORP) 4L acts as a scaffold protein assembling CD3-ε, G-α_q/11, and PLC-β3 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.-Cao, X., Chen, J., Li, D., Xie, P., Xu, M., Lin, W., Li, S., Pan, G., Tang, Y., Xu, J., Olkkonen, V. M., Yan, D., Zhong, W. ORP4L couples IP₃ to ITPR1 in control of endoplasmic reticulum calcium release.