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Occludin S408 phosphorylation regulates tight junction protein interactions and barrier function

2011; Rockefeller University Press; Volume: 193; Issue: 3 Linguagem: Inglês

10.1083/jcb.201010065

1540-8140

David R. Raleigh, Devin M. Boe, Dan Yu, Christopher R. Weber, Amanda M. Marchiando, Emily Bradford, Yingmin Wang, Licheng Wu, Eveline E. Schneeberger, Le Shen, Jerrold R. Turner,

Connexins and lens biology

Although the C-terminal cytoplasmic tail of the tight junction protein occludin is heavily phosphorylated, the functional impact of most individual sites is undefined. Here, we show that inhibition of CK2-mediated occludin S408 phosphorylation elevates transepithelial resistance by reducing paracellular cation flux. This regulation requires occludin, claudin-1, claudin-2, and ZO-1. S408 dephosphorylation reduces occludin exchange, but increases exchange of ZO-1, claudin-1, and claudin-2, thereby causing the mobile fractions of these proteins to converge. Claudin-4 exchange is not affected. ZO-1 domains that mediate interactions with occludin and claudins are required for increases in claudin-2 exchange, suggesting assembly of a phosphorylation-sensitive protein complex. Consistent with this, binding of claudin-1 and claudin-2, but not claudin-4, to S408A occludin tail is increased relative to S408D. Finally, CK2 inhibition reversed IL-13–induced, claudin-2–dependent barrier loss. Thus, occludin S408 dephosphorylation regulates paracellular permeability by remodeling tight junction protein dynamic behavior and intermolecular interactions between occludin, ZO-1, and select claudins, and may have therapeutic potential in inflammation-associated barrier dysfunction.