Calnexin and fatty acid binding protein 5 (Fabp5) complex in the blood-brain barrier

Abstract

Calnexin is a type 1 integral endoplasmic reticulum (ER) membrane protein and molecular chaperone involved in the folding and quality control of membrane associated and secreted proteins. The ER luminal domain of calnexin is responsible for the chaperone function, whereas the C-terminal domain is oriented to the cytoplasm and provides the link between ER luminal events and cytoplasmic signaling. This unique C-terminal domain of the protein undergoes distinct post-translational modifications including palmitoylation, SUMOylation and phosphorylation. In addition to that, the calnexin C-terminal domain interacts with various proteins including fatty acid binding protein 5 (Fabp5), a small (~15-kDa) cytoplasmic lipid chaperone that binds long-chain fatty acids and other hydrophobic ligands. We have discovered that multiple sclerosis (MS) patients have unusually high abundance of calnexin and Fabp5 in their blood-brain barrier (BBB) endothelial cells. The loss of either calnexin or Fabp5 in mice confers resistance to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Moreover, calnexin-deficient (Canx-/-) mice expressing a recombinant calnexin derivative that is missing the cytoplasmic C-terminal domain remain partially protected from EAE symptoms, indicating that deletion of the C-terminal domain alone, the site of the calnexin/Fabp5 complex formation, have protective effects against EAE symptoms. We identified that resistance to EAE in Canx-/- mice was due to inhibition of trans-endothelial T-cell migration across the brain endothelial cell monolayer when calnexin and Fabp5 complex formation is prevented. These findings uncovered the existence of an unanticipated link between the calnexin C-terminal domain/Fabp5 complex and EAE/MS pathogenesis.