title: PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy.
abstract: Prion protein modulates many cellular functions including the secretion of trophic factors by astrocytes. Some of these factors are found in exosomes, which are formed within multivesicular bodies (MVBs) and secreted into the extracellular space to modulate cell-cell communication. The mechanisms underlying exosome biogenesis were not completely deciphered. Here, we demonstrate that primary cultures of astrocytes and fibroblasts from prnp-null mice secreted lower levels of exosomes than wild-type cells. Furthermore, prnp-null astrocytes exhibited reduced MVB formation and increased autophagosome formation. The reconstitution of PRNP expression at the cell membrane restored exosome secretion in PRNP-deficient astrocytes, whereas macroautophagy/autophagy inhibition via BECN1 depletion reestablished exosome release in these cells. Moreover, the PRNP octapeptide repeat domain was necessary to promote exosome secretion and to impair the formation of the CAV1-dependent ATG12-ATG5 cytoplasmic complex that drives autophagosome formation. Accordingly, higher levels of CAV1 were found in lipid raft domains instead of in the cytoplasm in prnp-null cells. Collectively, these findings demonstrate that PRNP supports CAV1-suppressed autophagy to protect MVBs from sequestration into phagophores, thus facilitating exosome secretion.
authors.affiliation: a International Research Center , A.C. Camargo Cancer Center , São Paulo , Brazil , National Institute for Oncogenomics, INCITO.
authors.forename: Marcos V S
authors.initials: MV
authors.lastname: Dias
authors.affiliation: a International Research Center , A.C. Camargo Cancer Center , São Paulo , Brazil , National Institute for Oncogenomics, INCITO.
authors.forename: Bianca L
authors.initials: BL
authors.lastname: Teixeira
authors.affiliation: a International Research Center , A.C. Camargo Cancer Center , São Paulo , Brazil , National Institute for Oncogenomics, INCITO.
authors.forename: Bruna R
authors.initials: BR
authors.lastname: Rodrigues
authors.affiliation: b Electron Microscopy Center , Federal University of São Paulo , São Paulo , Brazil.
authors.forename: Rita
authors.initials: R
authors.lastname: Sinigaglia-Coimbra
authors.affiliation: c Paulo Niemeyer State Brain Institute , Rio de Janeiro , Brazil.
authors.forename: Isabel
authors.initials: I
authors.lastname: Porto-Carreiro
authors.affiliation: a International Research Center , A.C. Camargo Cancer Center , São Paulo , Brazil , National Institute for Oncogenomics, INCITO.
authors.forename: Martín
authors.initials: M
authors.lastname: Roffé
authors.affiliation: a International Research Center , A.C. Camargo Cancer Center , São Paulo , Brazil , National Institute for Oncogenomics, INCITO.
authors.forename: Glaucia N M
authors.initials: GN
authors.lastname: Hajj
authors.affiliation: a International Research Center , A.C. Camargo Cancer Center , São Paulo , Brazil , National Institute for Oncogenomics, INCITO.
authors.forename: Vilma R
authors.initials: VR
authors.lastname: Martins
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001343:Autophagy; D051242:Caveolin 1 / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism* / Q000648:ultrastructure; D008247:Lysosomes / Q000378:metabolism; D021962:Membrane Microdomains / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D057146:Multivesicular Bodies / Q000378:metabolism / Q000648:ultrastructure; D000072002:Prion Proteins / Q000737:chemistry / Q000378:metabolism*; D000072417:Protein Domains; D012091:Repetitive Sequences, Nucleic Acid; D013329:Structure-Activity Relationship
chemical_list: D051242:Caveolin 1; D000072002:Prion Proteins
keywords: autophagy; caveolin-1; exosomes; multivesicular bodies; prion protein