title: Degradation of aggregated LDL occurs in complex extracellular sub-compartments of the lysosomal synapse.
abstract: Monocyte-derived cells use an extracellular, acidic, lytic compartment (a lysosomal synapse) for initial degradation of large objects or species bound to the extracellular matrix. Akin to osteoclast degradation of bone, extracellular catabolism is used by macrophages to degrade aggregates of low density lipoprotein (LDL) similar to those encountered during atherogenesis. However, unlike osteoclast catabolism, the lysosomal synapse is a highly dynamic and intricate structure. In this study, we use high resolution three dimensional imaging to visualize compartments formed by macrophages to catabolize aggregated LDL. We show that these compartments are topologically complex, have a convoluted structure and contain sub-regions that are acidified. These sub-regions are characterized by a close apposition of the macrophage plasma membrane and aggregates of LDL that are still connected to the extracellular space. Compartment formation is dependent on local actin polymerization. However, once formed, compartments are able to maintain a pH gradient when actin is depolymerized. These observations explain how compartments are able to maintain a proton gradient while remaining outside the boundaries of the plasma membrane.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Rajesh K
authors.initials: RK
authors.lastname: Singh
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Valéria C
authors.initials: VC
authors.lastname: Barbosa-Lorenzi
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Frederik W
authors.initials: FW
authors.lastname: Lund
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Inna
authors.initials: I
authors.lastname: Grosheva
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA frmaxfie@med.cornell.edu.
authors.forename: Frederick R
authors.initials: FR
authors.lastname: Maxfield
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Abigail S
authors.initials: AS
authors.lastname: Haka
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism / Q000648:ultrastructure; D002788:Cholesterol Esters / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism* / Q000648:ultrastructure; D051379:Mice; D066329:Protein Aggregates; D055503:Protein Multimerization; D059748:Proteolysis; D000067996:RAW 264.7 Cells
chemical_list: D000199:Actins; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D066329:Protein Aggregates
keywords: Aggregated LDL; Extracellular catabolism; F-actin; Macrophage