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

  • Cell Rep. 2021 Jul 6;36(1):109327. doi: 10.1016/j.celrep.2021.109327.
Yaxiong Cui  1 ,  Yanxiao Wang  1 ,  Xiaopeng Song  1 ,  Huimin Ning  2 ,  Yizhe Zhang  1 ,  Yan Teng  1 ,  Jun Wang  3 ,  Xiao Yang  4
Affiliations
  • 1. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
  • 2. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China; Department of Immunology, College of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, China.
  • 3. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address: [email protected].
  • 4. State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address: [email protected].
PMID: 34233198 DOI: 10.1016/j.celrep.2021.109327
Abstract

The low level of transcytosis is a unique feature of cerebrovascular endothelial cells (ECs), ensuring restrictive blood-brain barrier (BBB) permeability. Major facilitator superfamily domain-containing 2a (MFSD2A) is a key regulator of the BBB function by suppressing caveolae-mediated transcytosis. However, the mechanisms regulating MFSD2A at the BBB have been barely explored. Here, we show that cerebrovascular EC-specific deletion of PTEN (Phosphatase and tensin homolog) results in a dramatic increase in vesicular transcytosis by the reduction of MFSD2A, leading to increased transcellular permeability of the BBB. Mechanistically, Akt signaling inhibits E3 ubiquitin Ligase NEDD4-2-mediated MFSD2A degradation. Consistently, cerebrovascular Nedd4-2 overexpression decreases MFSD2A levels, increases transcytosis, and impairs BBB permeability, recapitulating the phenotypes of Pten-deficient mice. Furthermore, Akt deletion decreases phosphorylated NEDD4-2 levels, restores MFSD2A levels, and normalizes BBB permeability in Pten-mutant mice. Altogether, our work reveals the essential physiological function of the PTEN/Akt/NEDD4-2/MFSD2A axis in the regulation of BBB permeability.

Keywords
MFSD2A; NEDD4-2; PTEN/AKT signaling; blood-brain barrier; brain endothelial cells; transcytosis.
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