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 (IP 3 )‐induced endoplasmic reticulum (ER) Ca 2+ 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 IP 3 receptor type 1 (ITPR1) in Jurkat T cells. ORP4L enables IP 3 binding to ITPR1; a truncated construct that lacks the ITPR1‐binding region retains the ability to increase IP 3 production but fails to mediate IP 3 and ITPR1 binding. In association with this ability of ORP4L, it enhances Ca 2+ release from the ER and subsequent cytosolic and mitochondrial parallel Ca 2+ 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 IP 3 and enables ER Ca 2+ 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 IP 3 to ITPR1 in control of endoplasmic reticulum calcium release. FASEB J. 33, 13852‐13865 (2019). www.fasebj.org