An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis.
An acquired phosphatidylinositol 4-phosphate transport initiates T-cell deterioration and leukemogenesis.
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获得性磷脂酰肌醇 4-磷酸转运引发 T 细胞退化和白血病发生
DOI：
10.1038/s41467-022-32104-7
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发表时间：
2022-07-29
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
脂质重塑是恶性细胞转化和肿瘤发生的关键，但涉及的精确分子过程和体内这些的直接证据仍然难以捉摸。在这里，我们报告说，氧固醇结合蛋白（OSBP）相关蛋白4 L（ORP 4L）表达在成人T细胞白血病（ATL）细胞，但不是正常的T细胞。在ORP 4L敲入的T细胞中，ORP 4L与OSBP二聚化以控制OSBP作为磷脂酰肌醇4-磷酸[PI（4）P]/胆固醇的交换剂在高尔基体和质膜（PM）之间的穿梭。通过这种转运机制到达PM的PI（4）P破坏磷脂酰肌醇4，5-二磷酸[PI（4，5）P2]和磷脂酰肌醇（3，4，5）三磷酸[PI（3，4，5）P3]的生物合成，从而在体外和体内促进PI 3 K/AKT过度活化和T细胞退化。ORP 4L和OSBP二聚化的破坏使PI（4）P转运和T细胞白血病发生失效。总之，我们确定了高尔基体和PM之间的非囊泡脂质转运机制，维持启动T细胞退化和白血病发生的致癌信号能力。氧化固醇结合蛋白相关蛋白4（ORP 4L）在T细胞急性淋巴细胞白血病中表达，是白血病发生所需的。在这里，作者表明ORP 4L协调磷脂PI（4）P从高尔基体到质膜的转运，有助于PI 3 K/AKT过度活化和T细胞白血病发生。
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. The oxysterol-binding protein-related protein 4 (ORP4L) is expressed in T-cell acute lymphoblastic leukemia and is required for leukemogenesis. Here the authors show that ORP4L orchestrates the transport of the phospholipid PI(4)P from Golgi to the plasma membrane, contributing to PI3K/AKT hyperactivation and T-cell leukemogenesis.
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影响因子：
11.4
作者：
Godfrey L;Crump NT;O'Byrne S;Lau IJ;Rice S;Harman JR;Jackson T;Elliott N;Buck G;Connor C;Thorne R;Knapp DJHF;Heidenreich O;Vyas P;Menendez P;Inglott S;Ancliff P;Geng H;Roberts I;Roy A;Milne TA
通讯作者：
Milne TA
影响因子：
7.5
作者：
Lees JA;Reinisch KM
通讯作者：
Reinisch KM
DOI：
10.1126/science.aab1370
发表时间：
2015-07-24
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chung J;Torta F;Masai K;Lucast L;Czapla H;Tanner LB;Narayanaswamy P;Wenk MR;Nakatsu F;De Camilli P
通讯作者：
De Camilli P
影响因子：
14.8
作者：
Burgett, Anthony W. G.;Poulsen, Thomas B.;Wangkanont, Kittikhun;Anderson, D. Ryan;Kikuchi, Chikako;Shimada, Kousei;Okubo, Shuichi;Fortner, Kevin C.;Mimaki, Yoshihiro;Kuroda, Minpei;Murphy, Jason P.;Schwalb, David J.;Petrella, Eugene C.;Cornella-Taracido, Ivan;Schirle, Markus;Tallarico, John A.;Shair, Matthew D.
通讯作者：
Shair, Matthew D.
影响因子：
11.2
作者：
Hosseini, Mohsen;Rezvani, Hamid Reza;Sarry, Jean-Emmanuel
通讯作者：
Sarry, Jean-Emmanuel