Enterocytes’ tight junctions: From molecules to diseases

Table 1 Distinctive characteristics of claudins

Claudin	Distinctive characteristics
1	Present in high resistance epithelia (collecting segment), absent in leaky epithelia (proximal tubule)
	Crucial for the mammalian epidermal barrier
	Mutations cause neonatal sclerosing cholangitis
	Prognostic value in colon and thyroid cancer
2	Present in leaky epithelia (proximal tubule) and absent in tight epithelia
	Present in the choroids plexus epithelium
3	Present in the tighter segments of the nephron
	Up-regulated in ovarian, breast, prostate and pancreatic tumors
4	Induces selective decrease in sodium permeability
	Present in the tighter segments of the nephron
	Alternative name: CPE-R
	Up-regulated in ovarian, breast, prostate and pancreatic tumors
5	Frequently deleted in velo cardio facial syndrome
	Constitutes TJ strands in endothelial cells and it is transiently expressed during the development of retinal pigment epithelium
6	Present in embryonic epithelia
	Its overexpression in transgenic mice generates a defective epidermal permeability barrier
7	Down regulated in head and neck squamous cell carcinomas
	Upregulated in stomach cancer
8	Present in the tighter segments of the nephron
10	Prognostic value in hepatocellular carcinoma (recurrence)
11	Present in oligodendrocytes and sertoli cells; also named OSP
14	Expressed in the sensory epithelium of the organ of Corti Mutations cause autosomal recessive deafness
15	Present in endothelial cells
16	Critical for Mg2+ and Ca2+ resorption in the human thick ascending limb of Henle
	Mutations cause familial hypomagnesaemia
18	Expressed in the lung and stomach

Claudins 9, 12, 13, 17, 19-24: Insufficient data. CPE-R: Clostridium perfringens enterotoxin receptor; OSP: Oligodendrocyte sertoli protein.

Table 2 Interaction between zonula occludens-1 and other macromolecules

ZO-1 protein domain	Interacting molecules
1st PDZ	C terminus of claudin
2nd/3rd PDZ	JAM
GUK	Occludin
	CAR
2nd PDZ	ZO-2s and ZO-3s 2nd PDZ
	Actin cytoskeleton
	Actin binding protein 4.1
	AF-6
	Cingulin
	A catenin
	Connexins 43 and 45

ZO: Zonula occludens; CAR: Coxsackievirus and adenovirus receptor; JAM: Junction adhesion molecule.

Table 3 Interaction between zonula occludens-2 and other macromolecules

ZO-2 binding area	Interacting molecule
1st PDZ	Claudin
2nd PDZ	ZO-1
GUK	Occludin
	Cingulin
C terminal proline rich domain	Actin
	Actin binding protein 4.1

ZO: Zonula occludens.

Table 4 Interaction between zonula occludens-3 and other macromolecules

ZO-3 binding sites	Interacting molecules
1st PDZ domain	Claudins
2nd PDZ domain	ZO-1
N terminus	Actin	Occludin
C terminus (class I PDZ binding motif TDL)	6th PDZ domain PATJ	Cingulin
	Connexin 45

ZO: Zonula occludens.

Table 5 Interaction between bacterial strains and tight junctional molecules

Vibrio cholerae[87,88]	It expresses zonula occludens toxin that reversibly increases paracellular permeability, triggering phospholipase C and protein kinase Ca dependent actin polymerization
	This process is primary or secondary related to TJ disruption
Shigella flexneri[89]	Secretes heat stable proteins that affect intestinal cells and lead to TJ disruption, even in the absence of living bacteria
Clostridium perfringens[29,31,61,62]	Its enterotoxin interacts with high affinity to claudin-4, therefore also known as CPE-R
	Lower affinity receptors are claudin-3 and occludin. CPE is proposed to be a multifunctional toxin that first induces cell damage at the level of the cell membrane, and thereby relates to TJ proteins, causing structural and functional alterations[61]
	Michl et al[31] have studied the effect of CPE on pancreatic cell cancers that expressed claudin 4[31], and they suggest that targeting of claudin-4 expressing tumors with CPE can represent a promising treatment method
Clostridium difficile[90]	This pathogenic microorganism, known etiologic factor of pseudomembranous colitis, secretes two toxins TcdA and TcdB that act through the Rho GTPase pathway to produce cell damage
	Study for their effect on epithelial TJ structure assumed that they lead to actin rearrangement, actin-ZO1 dissociation and dissociation of TJ components with changes of their cytoplasmic localization[90]
EPEC[91-93]	EPEC secretes through the type III secretion mechanism[87] the EspF protein, that is dose-dependently related to TER and epithelial barrier disruption and cytoplasmic localization of occludin[91]
	These effects seem to relate primary with phosphorylation of 20 kDa myosin light chain and cytoskeletal contraction. Occludin appears dephosphorylated on serine/threonine residues[92]
	The pathogenic action of EPEC on the intestinal epithelium is reversed by Saccharomyces boulardii[93]

CPE: Clostridium perfringens enterotoxin; CPE-R: Clostridium perfringens enterotoxin receptor; EPEC: Enteropathogenic Escherichia coli; TJ: Tight junction; ZO: Zonula occludens; GTPase: Guanosine triphosphatase.