9.B.41 The Occludin (Occludin) Family

The organization of metazoa is based on the formation of tissues and on tissue-typical functions, and these in turn are based on cell-cell connecting structures. In vertebrates, four major forms of cell junctions have been classified, and the molecular compositions of them have been elucidated (Franke, 2009). Desmosomes, which connect epithelial and some other cell types, and the almost ubiquitous adherens junctions are based on closely cis-packed glycoproteins, cadherins, which are associated head-to-head with those of the hemi-junction domain of an adjacent cell. Their cytoplasmic regions assemble sizable plaques of special proteins anchoring cytoskeletal filaments. Tight junctions (TJs) and gap junctions (GJs) are formed by tetraspan proteins (claudins and occludins, or connexins and innexins, respectively). They are arranged head-to-head as TJ seal bands or as paracrystalline connexin/innexin channels, allowing intercellular exchange of small molecules. The parallel discoveries of the four types of junctional protein families are described by Franke (2009) from a historical standpoint.

Occludins are constituents of tight junctions in animals and are unique markers of these structures. They are present in polarized endothelial and epithelial tissue barriers. Occludin is able to oligomerize and form tight junction strands by homologous and heterologous interactions, but it has no direct tightening function. They have been implicated in mediating the Leak Pathway of epithelial cells (Monaco et al. 2021). Its oligomerization is affected by pro- and antioxidative agents or processes. Phosphorylation of occludin has been described at multiple sites and is proposed to play a regulatory role in tight junction assembly and maintenance and, hence, to influence tissue barrier characteristics. Redox-dependent signal transduction mechanisms are among the pathways modulating occludin phosphorylation and function. Blasig et al. (2011) discussed the concept that occludin plays a key role in the redox regulation of tight junctions, which has a major impact in pathologies related to oxidative stress and corresponding pharmacologic interventions. The MARVEL transmembrane motif of occludin has been shown to mediate oligomerization and targeting of the protein to the basolateral surface in epithelia (Yaffe et al., 2012). Tetrandrine, a bisbenzyl isoquinoline alkaloid, attenuates intestinal epithelial barrier defects caused by colitis through promoting the expression of occludin (Chu et al. 2021).

No transport function is recognized for occludins, but a occludin/ZO-1 complex regulates the barrier function of tight junctions (Tash et al. 2012). These proteins are believed to form a superfamily together with claudins (1.H.1), connexins (1.A.24) and innexins (1.A.25) as well as others for a total of 15 families within the Tetraspan (4 TMS) Junctional Complex (4JC) Superfamily. (Chou et al. 2017). 

This family belongs to the Tetraspan Junctional Complex Protein or MARVEL (4JC) Superfamily.



Blasig, I.E., C. Bellmann, J. Cording, G. Del Vecchio, D. Zwanziger, O. Huber, and R.F. Haseloff. (2011). Occludin protein family: oxidative stress and reducing conditions. Antioxid Redox Signal 15: 1195-1219.

Chou, A., A. Lee, K.J. Hendargo, V.S. Reddy, M.A. Shlykov, H. Kuppusamykrishnan, A. Medrano-Soto, and M.H. Saier, Jr. (2017). Characterization of the Tetraspan Junctional Complex (4JC) superfamily. Biochim. Biophys. Acta. Biomembr 1859: 402-414.

Chu, Y., Y. Zhu, Y. Zhang, X. Liu, Y. Guo, L. Chang, X. Yun, Z. Wei, Y. Xia, and Y. Dai. (2021). Tetrandrine attenuates intestinal epithelial barrier defects caused by colitis through promoting the expression of Occludin via the AhR-miR-429 pathway. FASEB J. 35: e21502.

Cording, J., R. G√ľnther, E. Vigolo, C. Tscheik, L. Winkler, I. Schlattner, D. Lorenz, R.F. Haseloff, K.M. Schmidt-Ott, H. Wolburg, and I.E. Blasig. (2015). Redox Regulation of Cell Contacts by Tricellulin and Occludin: Redox-Sensitive Cysteine Sites in Tricellulin Regulate Both Tri- and Bicellular Junctions in Tissue Barriers as Shown in Hypoxia and Ischemia. Antioxid Redox Signal 23: 1035-1049.

Franke, W.W. (2009). Discovering the molecular components of intercellular junctions--a historical view. Cold Spring Harb Perspect Biol 1: a003061.

Jin, Y., I. Uchida, K. Eto, T. Kitano, and S. Abe. (2008). Size-selective junctional barrier and Ca2+-independent cell adhesion in the testis of Cynops pyrrhogaster: expression and function of occludin. Mol Reprod Dev 75: 202-216.

Monaco, A., B. Ovryn, J. Axis, and K. Amsler. (2021). The Epithelial Cell Leak Pathway. Int J Mol Sci 22:.

Riazuddin, S., Z.M. Ahmed, A.S. Fanning, A. Lagziel, S. Kitajiri, K. Ramzan, S.N. Khan, P. Chattaraj, P.L. Friedman, J.M. Anderson, I.A. Belyantseva, A. Forge, S. Riazuddin, and T.B. Friedman. (2006). Tricellulin is a tight-junction protein necessary for hearing. Am J Hum Genet 79: 1040-1051.

Tash, B.R., M.C. Bewley, M. Russo, J.M. Keil, K.A. Griffin, J.M. Sundstrom, D.A. Antonetti, F. Tian, and J.M. Flanagan. (2012). The occludin and ZO-1 complex, defined by small angle X-ray scattering and NMR, has implications for modulating tight junction permeability. Proc. Natl. Acad. Sci. USA 109: 10855-10860.

Yaffe, Y., J. Shepshelovitch, I. Nevo-Yassaf, A. Yeheskel, H. Shmerling, J.M. Kwiatek, K. Gaus, M. Pasmanik-Chor, and K. Hirschberg. (2012). The MARVEL transmembrane motif of occludin mediates oligomerization and targeting to the basolateral surface in epithelia. J Cell Sci 125: 3545-3556.


TC#NameOrganismal TypeExample

Occludin (with residues 70-220 comprising a MARVEL domain, and residues 430-520 comprising an Occludin_ELL domain.


Occludin of Homo sapiens (Q16625)


Occludin-like protein

Cichlid fish

Occludin-like protein of Oreochromis niloticus (Tilopia nilotica) (I3JWG5)


Chicken occludin.  May play a role in the formation and regulation of the tight junction (TJ) paracellular permeability barrier. Interacts with ZO-1 (Jin et al., 2008).


Occludin of Gallus gallus (chicken)


Putative occludin of 483 aas.


Occludin of Takifugu rubripes (Japanese pufferfish) (Fugu rubripes)


TC#NameOrganismal TypeExample

MARVEL domain-containing protein 2, tricellulin, of 558 aas and 4 TMSs.  Plays a role in the formation of tight junctions in epithelial barriers. The separation of the endolymphatic and perilymphatic spaces of the organ of Corti from one another by epithelial barriers is required for normal hearing (Riazuddin et al. 2006).  Tricellulin forms tight junctions and is a junctional redox regulator (Cording et al. 2015).

Tricellulin of Homo sapiens


Uncharacterized occludin homologue

UP of Meleagris gallopavo (Common turkey)


TC#NameOrganismal TypeExample