Cytoplasmic phospholipase A2 antagonists inhibit multiple endocytic membrane trafficking pathways
Anne M Doody1, Amy L Antosh, William J Brown
1Department of Molecular Biology and Genetics, Cornell University, Biotechnology Building, Ithaca, NY 14853, USA.
Biochemical and Biophysical Research Communications
|August 22, 2009
Summary
Cytosolic phospholipase A(2) (PLA(2)) activity is essential for endocytic trafficking. Inhibiting PLA(2) disrupts the recycling and degradation of key cellular components, indicating a general role in membrane tubule formation for cargo export.
Area of Science:
- Cell Biology
- Molecular Biology
- Biochemistry
Background:
- Cytosolic Ca(2+)-independent phospholipase A(2) (PLA(2)) activity has been implicated in endosome membrane tubule formation.
- This process is crucial for the export of transferrin (Tf) and transferrin receptors (TfR) from sorting endosomes (SEs) and the endocytic recycling compartment (ERC).
Purpose of the Study:
- To investigate the general role of PLA(2) activity in endocytic trafficking pathways.
- To determine if PLA(2) is required for the export of various cargoes from endosomes.
Main Methods:
- Utilized the reversible cytoplasmic PLA(2) antagonist ONO-RS-082 (ONO).
- Assessed the impact of ONO on the endocytic recycling of low-density lipoprotein receptor (LDLR) and TfRs.
- Evaluated the effect of ONO on the degradative pathways of low-density lipoprotein (LDL) and epidermal growth factor (EGF).
Main Results:
- ONO-RS-082 demonstrated a concentration-dependent, differential block in endocytic recycling of LDLR and TfRs.
- The antagonist also inhibited the degradative pathways of LDL and EGF.
- These findings suggest a broad requirement for PLA(2) in endocytic transport.
Conclusions:
- Cytosolic PLA(2) activity plays a general role in endocytic trafficking.
- PLA(2) mediates the formation of membrane tubules necessary for cargo export from multiple endocytic compartments.
- This highlights PLA(2) as a key regulator of cellular uptake and transport pathways.
Related Concept Videos
01:42Phosphoinositides and PIPs
Phosphoinositides are a group of phospholipids containing a glycerol backbone with two fatty acid chains and a phosphate attached to a myoinositol sugar ring. The inositol head group extends into the cytoplasm, where it is modified by adding phosphate groups to form phosphatidylinositol phosphates or PIPs.
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
Different phosphoinositides are synthesized and recruited on the cytosolic face of the plasma membrane. The localization of specific phosphoinositides concentrated in separate membrane...
01:19Membrane Asymmetry Regulating Transporters
Enzymes like flippase, floppase, and scramblase transfer phospholipids from one layer to another in the membrane, thereby affecting membrane asymmetry.
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
Flippase
Eukaryotic flippases are type-IV P-type ATPases or P4-ATPases belonging to P-type ATPase family proteins that are membrane-bound pumps involved in the ATP-mediated transport of ions and molecules across the membrane. Flippases flip specific phospholipids from the outer to the inner leaflet of a membrane. All P4-ATPases have one...
01:11IP3/DAG Signaling Pathway
Membrane lipids such as phosphatidylinositol (PI) are precursors for several membrane-bound and soluble second messengers. Specific kinases phosphorylate PI and produce phosphorylated inositol phospholipids. One such inositol phospholipids are the phosphatidylinositol-4,5 bisphosphate [PI(4,5)P2], present in the inner half of the lipid bilayer. Upon ligand binding, GPCR stimulates Gq proteins to turn on phospholipase Cꞵ. Activated phospholipase Cꞵ cleaves PI(4,5)P2 and produces two-second...
01:38Receptor-mediated Endocytosis
Overview
01:20Receptor-mediated Endocytosis
Receptor-mediated endocytosis is when bulk amounts of specific molecules are imported into a cell after binding to cell surface receptors. The molecules bound to these receptors are taken into the cell through inward folding of the cell surface membrane, which is eventually pinched off into a vesicle within the cell. Structural proteins, such as clathrin, coat the budding vesicle.
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
Clathrin-Mediated Endocytosis of LDL
One well-characterized example of receptor-mediated endocytosis is the...
00:58Recycling Endosomes and Transcytosis
The recycling endosome, also known as the endosomal recycling compartment (ERC), is a part of the slow-recycling process of the endocytic pathway. Molecules internalized through receptor-mediated endocytosis are either degraded in the lysosomes or are recycled to the plasma membrane through the fast- or slow-recycling route.
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...
The recycling endosome is not a single organelle but an extensively tubulated network of recycling pathways. It functions in storing molecules or transporting them across...