PRNP/prion protein regulates the secretion of exosomes modulating CAV1/caveolin-1-suppressed autophagy

Autor(es)

Dias, Marcos V. S. ; Teixeira, Bianca L. ; Rodrigues, Bruna R. ; Sinigaglia-Coimbra, Rita ; Porto-Carreiro, Isabel ; Roffe, Martin ; Hajj, Glaucia N. M. ; Martins, Vilma R.

• Tipo de documento: Artigo Científico
• Fonte: AUTOPHAGY; v. 12, n. 11, p. 2113-2128, 2016.
• Citações Web of Science: 15

Resumo

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. (AU)

• Processo FAPESP: 12/19019-0 - Regulação da atividade de STAT3 e o papel da proteína STI1/Hop secretada em glioblastoma multiforme
• Beneficiário: Bruna Roz Rodrigues
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 10/19200-1 - IDENTIFICAÇÃO DOS MECANISMOS DE SECREÇÃO DA PROTEÍNA STI1/Hop
• Beneficiário: Marcos Vinicios Salles Dias
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 09/14027-2 - Mecanismos associados à função da proteína prion e seu ligante STI1/Hop: abordagens terapêuticas
• Beneficiário: Vilma Regina Martins
• Modalidade de apoio: Auxílio à Pesquisa - Temático