Prnp/prion protein regulates the secretion of exosomes modulating cav1/caveolin-1-suppressed autophagy

Prnp/prion protein regulates the secretion of exosomes modulating cav1/caveolin-1-suppressed autophagy

Author Dias, Marcos V. S. Google Scholar
Teixeira, Bianca L. Google Scholar
Rodrigues, Bruna R. Google Scholar
Sinigaglia-Coimbra, Rita Autor UNIFESP Google Scholar
Porto-Carreiro, Isabel Google Scholar
Roffe, Martin Google Scholar
Hajj, Glaucia N. M. Google Scholar
Martins, Vilma R. Google Scholar
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.
Keywords Autophagy
Caveolin-1
Exosomes
Multivesicular Bodies
Prion ProteinCellular Prion Protein
Stress-Inducible Protein-1
Extracellular Vesicles
Neurite Outgrowth
Multivesicular Bodies
Monitoring Autophagy
Molecular-Mechanisms
Neuronal Survival
Lipid Rafts
Cells
Language English
Sponsor Fundacao de Amparo a Pesquisa do Estado de Sao Paulo [FAPESP 09/14027-2]
Conselho Nacional de Desenvolvimento Cientifico e Tecnologico [CNPq 467566/2014-3]
FAPESP [2010/19200-1, 2012/19019-0]
Grant number FAPESP: 09/14027-2
CNPq
FAPESP: 2010/19200-1
FAPESP: 2012/19019-0
Date 2016
Published in Autophagy. Philadelphia, v. 12, n. 11, p. 2113-2128, 2016.
ISSN 1554-8627 (Sherpa/Romeo, impact factor)
Publisher Univ Federal Juiz Fora, Campus Univ
Extent 2113-2128
Origin https://doi.org/10.1080/15548627.2016.1226735
Access rights Open access Open Access
Type Article
Web of Science ID WOS:000387665000012
URI http://repositorio.unifesp.br/handle/11600/49350

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