The dual role of zonula occludens (ZO) proteins

Abstract

ZO (zonula occludens) proteins are scaffolding proteins providing the structural basis for the assembly of multiprotein complexes at the cytoplasmic surface of intercellular junctions. In addition, they provide a link between the integral membrane proteins and the filamentous cytoskeleton. ZO proteins belong to the large family of membrane-associated guanylate kinase (MAGUK)-like proteins comprising a number of subfamilies based on domain content and sequence similarity. Besides their structural function at cell-cell contacts, ZO proteins appear to participate in the regulation of cell growth and proliferation. Detailed molecular studies have shown that ZO proteins exhibit conserved functional nuclear localization and nuclear export motifs within their amino acid sequence. Further, ZO proteins interact with dual residency proteins localizing to the plasma membrane and the nucleus. Although the nuclear targeting of ZO proteins has well been described, many questions concerning the biological significance of this process have remained open. This review focuses on the dual role of ZO proteins, being indispensable structural components at the junctional site and functioning in signal transduction pathways related to gene expression and cell behavior.

Figure 1

Localization of zonula occludens (ZO) proteins at tight junctions (TJs). Transmembrane components of TJs interact at least with one ZO protein. As mentioned in the text, only ZO-1 and ZO-2 localize to the nucleus, while nuclear targeting of ZO-3 has not been observed so far. Already described interactions of ZO proteins with other types of junctions is not included here. TJs: tight junctions; AJs: adherens junctions; DM: desmosomes; GJs: gap junctions; CAR: coxsackievirus and adenovirus receptor.

Figure 2

ZO proteins interact with transmembrane proteins and with peripheral cytoplasmic proteins at the junctional site. Details are mentioned in the text. Some proteins interacting with ZO proteins are not included in the figure since their association domain is less well described. These include CAR (coxsackievirus and adenovirus receptor), tricellulin, and cingulin. ABR: actin binding region; AF-6: ALL-1 fusion partner at chromosome 6; Apg-2: (ATP and peptide-binding protein in germ cells)-2; Cx: Connexin; Ga12: G protein α 12 subunit; GUK: Guanylate kinase-like domain; JAM: Junction adhesion molecule; hScrib: human Scribble; PATJ: Protein associated with tight junctions; P-P-P: Proline-rich region; PDZ: Psd95/discs large/zonula occludens-1 domain; SAF-B: Scaffold attachment factor-B; SH3: Src homology3 domain; U1-U6: Unique variable domains; ZAK: ZO-1 associated kinase; ZONAB: ZO-1 associated nucleic acid binding protein; ZU5: Domain present in ZO-1 and Unc5-like netrin receptors.

Figure 3

(a) Summary of “dual residency proteins” (locating at the plasma membrane and at the nucleus) associating with ZO-proteins at the junctional site. (b) Nuclear interactions of ZO proteins. ZONAB: ZO-1 associated nucleic acid binding protein; Cdk-4: Cyclin-dependent kinase-4; ARVCF: Armadillo repeat gene deleted in velo-cardio-facial syndrome; SC35: Splicing factor 35.