title: Adaptor Protein CD2AP and L-type Lectin LMAN2 Regulate Exosome Cargo Protein Trafficking through the Golgi Complex.
abstract: Exosomes, 40-150-nm extracellular vesicles, transport biological macromolecules that mediate intercellular communications. Although exosomes are known to originate from maturation of endosomes into multivesicular endosomes (also known as multivesicular bodies) with subsequent fusion of the multivesicular endosomes with the plasma membrane, it remains unclear how cargos are selected for exosomal release. Using an inducible expression system for the exosome cargo protein GPRC5B and following its trafficking trajectory, we show here that newly synthesized GPRC5B protein accumulates in the Golgi complex prior to its release into exosomes. The L-type lectin LMAN2 (also known as VIP36) appears to be specifically required for the accumulation of GPRC5B in the Golgi complex and restriction of GPRC5B transport along the exosomal pathway. This may occur due to interference with the adaptor protein GGA1-mediated trans Golgi network-to-endosome transport of GPRC5B. The adaptor protein CD2AP-mediated internalization following cell surface delivery appears to contribute to the Golgi accumulation of GPRC5B, possibly in parallel with biosynthetic/secretory trafficking from the endoplasmic reticulum. Our data thus reveal a Golgi-traversing pathway for exosomal release of the cargo protein GPRC5B in which CD2AP facilitates the entry and LMAN2 impedes the exit of the flux, respectively.
authors.affiliation: From the Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina 29425, kwonk@musc.edu.
authors.forename: Sang-Ho
authors.initials: SH
authors.lastname: Kwon
authors.affiliation: the Department of Radiology, Stanford Cardiovascular Institute, and.|Department of Neurology and Neurological Sciences,Stanford University School of Medicine, Stanford, California 94305.
authors.forename: Sekyung
authors.initials: S
authors.lastname: Oh
authors.affiliation: the Departments of Anatomy and Biochemistry/Biophysics, University of California, San Francisco, California 94143, and.
authors.forename: Marisa
authors.initials: M
authors.lastname: Nacke
authors.affiliation: the Departments of Anatomy and Biochemistry/Biophysics, University of California, San Francisco, California 94143, and.
authors.forename: Keith E
authors.initials: KE
authors.lastname: Mostov
authors.affiliation: From the Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina 29425.|the Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401.
authors.forename: Joshua H
authors.initials: JH
authors.lastname: Lipschutz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001693:Biological Transport, Active / Q000502:physiology; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004285:Dogs; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D037241:Mannose-Binding Lectins / Q000235:genetics / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; C114545:CD2-associated protein; D003598:Cytoskeletal Proteins; C407306:GGA adaptor proteins; C410799:GPRC5B protein, human; C086797:LMAN2 protein, human; D037241:Mannose-Binding Lectins; D026901:Membrane Transport Proteins; D043562:Receptors, G-Protein-Coupled
keywords: CD2AP; G protein-coupled receptor (GPCR); Golgi; LMAN2; endosome; exosomes; extracellular vesicles; membrane trafficking; multivesicular; urinary proteins