An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis

Wenbin Zhong, Weize Lin, Yingjie Yang, Dan Chen, Xiuye Cao, Mengyang Xu, Guoping Pan, Huanzhao Chen, Jie Zheng, Xiaoqin Feng, Li hua Yang, Chaofeng Lai, Vesa M. Olkkonen, Jun Xu, Shuzhong Cui () and Daoguang Yan ()
Additional contact information
Wenbin Zhong: Jinan University
Weize Lin: Jinan University
Yingjie Yang: Jinan University
Dan Chen: Jinan University
Xiuye Cao: Jinan University
Mengyang Xu: Jinan University
Guoping Pan: Jinan University
Huanzhao Chen: Jinan University
Jie Zheng: Jinan University
Xiaoqin Feng: Southern Medical University
Li hua Yang: Southern Medical University
Chaofeng Lai: Jinan University
Vesa M. Olkkonen: Minerva Foundation Institute for Medical Research, Biomedicum 2U
Jun Xu: Sun Yat-Sen University
Shuzhong Cui: Affiliated Cancer Hospital and Institute of Guangzhou Medical University
Daoguang Yan: Jinan University

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Lipid remodeling is crucial for malignant cell transformation and tumorigenesis, but the precise molecular processes involved and direct evidences for these in vivo remain elusive. Here, we report that oxysterol-binding protein (OSBP)-related protein 4 L (ORP4L) is expressed in adult T-cell leukemia (ATL) cells but not normal T-cells. In ORP4L knock-in T-cells, ORP4L dimerizes with OSBP to control the shuttling of OSBP between the Golgi apparatus and the plasma membrane (PM) as an exchanger of phosphatidylinositol 4-phosphate [PI(4)P]/cholesterol. The PI(4)P arriving at the PM via this transport machinery replenishes phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] and phosphatidylinositol (3,4,5) trisphosphate [PI(3,4,5)P3] biosynthesis, thus contributing to PI3K/AKT hyperactivation and T-cell deterioration in vitro and in vivo. Disruption of ORP4L and OSBP dimerization disables PI(4)P transport and T-cell leukemogenesis. In summary, we identify a non-vesicular lipid transport machinery between Golgi and PM maintaining the oncogenic signaling competence initiating T-cell deterioration and leukemogenesis.

Date: 2022
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DOI: 10.1038/s41467-022-32104-7

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