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.

LMP1‐positive extracellular vesicles promote radioresistance in nasopharyngeal carcinoma cells through P38 MAPK signaling

“…However, the mechanisms of LMP1 trafficking into EVs have not been clarified yet. Several studies have proposed that CD63 may account for the mechanism of LMP1 incorporation into EVs and that caveolin is responsible for EV secretion . We still believe that more investigations are needed to further uncover the mechanisms of LMP1 trafficking into EVs.…”

To be or not to be... secreted as exosomes, a balance finely tuned by the mechanisms of biogenesis

“…Therefore, a similar balance between exosome secretion and autophagy may exist and would be dependent on external stimuli such as starvation. Supporting this hypothesis, it has been shown that the prion protein (PrP) can promote exosome secretion by inhibiting autophagosome formation through interaction with caveolin 1, a suppressor of autophagosome formation (87).…”

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…Conversely, exosome release is stimulated by inhibition of mTORC1 by rapamycin or nutrient and growth factor deprivation (Zou et al, 2019). Inhibition of autophagy by wortmannin or CRISPR/Cas9-mediated knockout of the autophagy protein Atg5 (autophagy-related 5) in neuronal cell lines increased the release of exosomes, documenting this interrelationship in neurons as well as other cell types (Dias et al, 2016).…”