PDF(Pubmed)
Abstract：
T-cell acute lymphoblastic leukemia (T-ALL) is one of the deadliest and most aggressive hematological malignancies, but its pathological mechanism in controlling cell survival is not fully understood. Oculocerebrorenal syndrome of Lowe is a rare X-linked recessive disorder characterized by cataracts, intellectual disability, and proteinuria. This disease has been shown to be caused by mutation of oculocerebrorenal syndrome of Lowe 1 (OCRL1; OCRL), encoding a phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] 5-phosphatase involved in regulating membrane trafficking; however, its function in cancer cells is unclear. Here, we uncovered that OCRL1 is overexpressed in T-ALL cells, and knockdown of OCRL1 results in cell death, indicating the essential role of OCRL in controlling T-ALL cell survival. We show OCRL is primarily localized in the Golgi and can translocate to plasma membrane (PM) upon ligand stimulation. We found OCRL interacts with oxysterol-binding protein-related protein 4L, which facilitates OCRL translocation from the Golgi to the PM upon cluster of differentiation 3 stimulation. Thus, OCRL represses the activity of oxysterol-binding protein-related protein 4L to prevent excessive PI(4,5)P2 hydrolysis by phosphoinositide phospholipase C β3 and uncontrolled Ca2+ release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P2 in the PM, disrupting the normal Ca2+ oscillation pattern in the cytosol and leading to mitochondrial Ca2+ overloading, ultimately causing T-ALL cell mitochondrial dysfunction and cell death. These results highlight a critical role for OCRL in maintaining moderate PI(4,5)P2 availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.
摘要：
T细胞急性淋巴细胞白血病（T-ALL）是最致命和最具侵袭性的血液系统恶性肿瘤之一，但其控制细胞存活的病理机制尚不完全清楚。眼脑肾综合征（也称为Lowe综合征）是一种罕见的X连锁隐性疾病，以白内障为特征，智力残疾,和蛋白尿。该疾病已被证明是由Lowe1（OCRL1;OCRL）的眼脑肾综合征突变引起的，编码参与调节膜运输的磷脂酰肌醇4,5-二磷酸[PI（4,5）P2]5-磷酸酶，然而,其在癌细胞中的功能尚不清楚。这里,我们发现OCRL1在T-ALL细胞中过表达，敲低OCRL1会导致细胞死亡，表明OCRL在控制T-ALL细胞存活中的重要作用。我们显示OCRL主要位于高尔基体中，并且可以在配体刺激后易位到质膜(PM)。我们发现OCRL与OSBP相关蛋白4L（ORP4L）相互作用，这有助于OCRL在分化簇3(CD3)刺激后从高尔基体易位到PM。因此，OCRL抑制ORP4L的活性，以防止磷酸肌醇磷脂酶Cβ3（PLCβ3）过度水解PI（4,5）P2和内质网（ER）不受控制的Ca2释放。我们提出OCRL1缺失导致PI(4,5)P2在PM中积累，破坏细胞质中正常的Ca2+振荡模式，导致线粒体Ca2+过载，最终导致T-ALL细胞线粒体功能障碍和细胞死亡。这些结果突出了OCRL在维持T-ALL细胞中中等PI(4,5)P2可用性中的关键作用。我们的发现还提高了靶向OCRL1治疗T-ALL疾病的可能性。
