Occludin: one protein, many forms

Abstract

Intercellular tight junctions (TJs) exhibit a complex molecular architecture involving the regulated cointeraction of cytoplasmic adaptor proteins (e.g., zonula occludens) and integral membrane linker proteins (e.g., occludin and claudins). They provide structural integrity to epithelial and endothelial tissues and create highly polarized barriers essential to homeostatic maintenance within vertebrate physiological systems, while their dysregulation is an established pathophysiological hallmark of many diseases (e.g., cancer, stroke, and inflammatory lung disease). The junctional complex itself is a highly dynamic signaling entity wherein participant proteins constantly undergo a blend of regulatory modifications in response to diverse physiological and pathological cues, ultimately diversifying the overall adhesive properties of the TJ. Occludin, a 65-kDa tetraspan integral membrane protein, contributes to TJ stabilization and optimal barrier function. This paper reviews our current knowledge of how tissue occludin is specifically modified at the posttranscriptional and posttranslational levels in diverse circumstances, with associated consequences for TJ dynamics and epithelial/endothelial homeostasis. Mechanistic concepts such as splice variance and alternate promoter usage, proteolysis, phosphorylation, dimerization, and ubiquitination are comprehensively examined, and possible avenues for future investigation highlighted.

Fig 1

Plasma membrane-associated human occludin. Individual occludin domains (and amino acid lengths) are indicated. C-terminal occludin interaction with the ZO-1 GUK domain is also shown (Note that ZO-1 PDZ domains indicated are believed to mediate ZO-1 interaction with claudins.) ZO-1 is not to scale (∼25% of actual protein size). EL1/2, extracellular loops 1 and 2; GUK, guanylate kinase domain; IL, intracellular loop; SH3, Src homology 3 domain; TM1 to -4, transmembrane domains 1 to 4.

Fig 2

Structural organization of the TM4(+) and TM4(−) variants of human occludin protein. Canonical/TM4(+) occludin is pictured. Also pictured is the 54-aa deletion corresponding to the TM4(−) variant resulting from skipping of exon 4. C⁴⁰⁹, cysteine-409; EL1/2, extracellular loops 1 and 2 (EL1 is glycine/tyrosine rich); IL, intracellular loop; M1, methionine-1; PY, Nedd4-2-binding domain; T⁵²², threonine-522; TM1 to -4, transmembrane domains 1 to 4; Y^398/402, tyrosine-398/402; WW, Itch-binding domain.