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Merck

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

Nature communications (2022-07-30)
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, Daoguang Yan
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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 4โ€‰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.

MATERIALS
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Roche
cOmpleteโ„ข, Mini, EDTA-free Protease Inhibitor Cocktail, Protease Inhibitor Cocktail Tablets provided in a glass vial, Tablets provided in a glass vial
Sigma-Aldrich
Anti-OSBP2 antibody produced in rabbit, Prestige Antibodiesยฎ Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution