Back to Search
Start Over
Oculocerebrorenal syndrome of Lowe (OCRL) controls leukemic T-cell survival by preventing excessive PI(4,5)P 2 hydrolysis in the plasma membrane.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2023 Jun; Vol. 299 (6), pp. 104812. Date of Electronic Publication: 2023 May 11. - Publication Year :
- 2023
-
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)P <subscript>2</subscript> ] 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)P <subscript>2</subscript> hydrolysis by phosphoinositide phospholipase C β3 and uncontrolled Ca <superscript>2+</superscript> release from the endoplasmic reticulum. We propose OCRL1 deletion leads to accumulation of PI(4,5)P <subscript>2</subscript> in the PM, disrupting the normal Ca <superscript>2+</superscript> oscillation pattern in the cytosol and leading to mitochondrial Ca <superscript>2+</superscript> 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)P <subscript>2</subscript> availability in T-ALL cells. Our findings also raise the possibility of targeting OCRL1 to treat T-ALL disease.<br />Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.<br /> (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
- Subjects :
- Humans
Cell Survival
Hydrolysis
Oculocerebrorenal Syndrome enzymology
Oculocerebrorenal Syndrome genetics
Golgi Apparatus metabolism
Ligands
Protein Transport
Calcium Signaling
Mitochondria metabolism
Mitochondria pathology
Cytosol metabolism
Cell Membrane metabolism
Phosphatidylinositol 4,5-Diphosphate metabolism
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma immunology
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
T-Lymphocytes cytology
T-Lymphocytes immunology
Phosphoric Monoester Hydrolases biosynthesis
Phosphoric Monoester Hydrolases deficiency
Phosphoric Monoester Hydrolases genetics
Phosphoric Monoester Hydrolases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 299
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 37172724
- Full Text :
- https://doi.org/10.1016/j.jbc.2023.104812