Brain endothelial PTEN/AKT/NEDD4-2/MFSD2A axis regulates blood-brain barrier permeability

Abstract

Highlights d Endothelial PTEN/AKT signaling regulates BBB permeability by suppressing transcytosis d Pten loss in brain ECs leads to increased transcellular permeability of the BBB d PTEN/AKT signaling inhibits E3 ubiquitin ligase NEDD4-2mediated MFSD2A degradation d Akt1 deletion rescues BBB abnormalities in Pten-mutant mice

Autophagic degradation of claudin‐5 mediated by its binding to a Clostridium perfringens enterotoxin fragment modulates endothelial barrier permeability

“…It is reported that upregulation of caveolin‐1, which inhibits PTEN/AKT/mTOR signalling, is able to promote autophagy in non‐alcoholic fatty liver disease (NAFLD) mice [35]. Interestingly, it has also been reported that caveolin‐1‐related transcytosis, which is upregulated by PTEN/AKT signalling, increase trafficking across the BBB, thus increasing transcellular BBB permeability [36]. The involvement of PTEN/AKT/mTOR signalling pathway during the caveolin‐1‐mediated transcytosis of membranous claudin‐5 and the detailed molecular mechanisms in cCPE YWSH ‐mediated opening of BBB require more in‐depth analysis.…”

The blood-brain barrier in health, neurological diseases, and COVID-19

“…As a newly identified essential inhibitor of BBB transcytosis, major facilitator superfamily domain-containing protein 2a (Mfsd2a) functions as a lipid transporter for the omega-3 fatty acid docosahexaenoic acid ( Fig. 2 ) [ 41 , 44 , 45 ]. Loss of Mfsd2a in mice led to increased permeability of BBB due to upregulated transcytosis [45] .…”

“…2 ) [ 41 , 44 , 45 ]. Loss of Mfsd2a in mice led to increased permeability of BBB due to upregulated transcytosis [45] . The most recent structural definition of Mfsd2a increases the potential to modulate the BBB permeability by targeting Mfsd2a for efficient drug delivery [44] .…”

Transcellular routes of blood–brain barrier disruption

“…Recent work has implicated phosphatase and tensin homolog (PTEN)/AKT signaling through the E3 ubiquitin ligase NEDD4-2 as an important regulatory pathway for Mfsd2a expression and caveolae suppression. 66 PTEN is a phosphatase that inhibits AKT activity, thus reducing the phosphorylation and ubiquitin ligase activity of NEDD4-2 and increasing Mfsd2a stability. Brain endothelial cell-specific deletion of PTEN results in decreased Mfsd2a and increased formation of caveolar vesicles.…”

“…Brain endothelial cell-specific deletion of PTEN results in decreased Mfsd2a and increased formation of caveolar vesicles. 66 However, another group has shown that brain injury causes the upregulation of PTEN, and that pharmacological PTEN inhibition reduces BBB disruption and improves functional outcomes postinjury. 67 It is possible that these apparently conflicting results could be due to differences in cell-type specific functions, or harmful functions of PTEN in an injury context.…”