Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization

Gong, Y.; Renigunta, Vijayaram; Zhou, Yi; Sunq, Abby; Wang, Jinzhi; Yang, Jing; Renigunta, Aparna; Baker, Lane A.; Hou, Jianghui

doi:10.1091/mbc.e15-06-0422

Cited by 60 publications

(60 citation statements)

References 43 publications

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“…The finding that cldn16 and cldn19 can interact in cis but not in trans is in accordance with previous findings based on Y2H assays showing the same outcome (17,34). These studies demonstrated that cldn16 and cldn19 can form a stable dimer through the cis association of transmembrane segments 3 and 4 (34). The dependence of cldn16 TJ localization on coexpression and interaction with cldn19 is in good agreement with the finding that CLDN19 defects in humans and mice develop a phenotype similar to that of CLDN16 mutations (13)(14)(15)(16)18).…”

Section: Discussionsupporting

confidence: 93%

“…Its integration in TAL TJs presumably is facilitated by the heteromeric interaction with cldn19 that also interacts with cldn3 and thus allows the formation of the cldn3/16/19 TJ complex. The finding that cldn16 and cldn19 can interact in cis but not in trans is in accordance with previous findings based on Y2H assays showing the same outcome (17,34). These studies demonstrated that cldn16 and cldn19 can form a stable dimer through the cis association of transmembrane segments 3 and 4 (34).…”

Section: Discussionsupporting

confidence: 92%

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Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Milatz

Himmerkus

Wulfmeyer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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181

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The thick ascending limb (TAL) of Henle's loop drives paracellular Na + , Ca 2+ , and Mg 2+ reabsorption via the tight junction (TJ). The TJ is composed of claudins that consist of four transmembrane segments, two extracellular segments (ECS1 and -2), and one intracellular loop. Claudins interact within the same (cis) and opposing (trans) plasma membranes. The claudins Cldn10b, -16, and -19 facilitate cation reabsorption in the TAL, and their absence leads to a severe disturbance of renal ion homeostasis. We combined electrophysiological measurements on microperfused mouse TAL segments with subsequent analysis of claudin expression by immunostaining and confocal microscopy. Claudin interaction properties were examined using heterologous expression in the TJ-free cell line HEK 293, live-cell imaging, and Förster/FRET. To reveal determinants of interaction properties, a set of TAL claudin protein chimeras was created and analyzed. Our main findings are that (i) TAL TJs show a mosaic expression pattern of either cldn10b or cldn3/cldn16/cldn19 in a complex; (ii) TJs dominated by cldn10b prefer Na + over Mg 2+ , whereas TJs dominated by cldn16 favor Mg 2+ over Na + ; (iii) cldn10b does not interact with other TAL claudins, whereas cldn3 and cldn16 can interact with cldn19 to form joint strands; and (iv) further claudin segments in addition to ECS2 are crucial for trans interaction. We suggest the existence of at least two spatially distinct types of paracellular channels in TAL: a cldn10b-based channel for monovalent cations such as Na + and a spatially distinct site for reabsorption of divalent cations such as Ca 2+ and Mg 2+ .T he kidney regulates the salt and water balance of the body by filtration and subsequent reabsorption or secretion of ions and water. Thereby it controls blood pressure and maintains acid-base homeostasis. The thick ascending limb (TAL) of Henle's loop drives reabsorption of Na + , Cl − , Ca 2+ , and Mg 2+ from the tubular fluid into the blood. Na + and Cl − are reabsorbed via the transcellular pathway, involving the renal-specific isoform of the Na + /K + /2Cl − cotransporter (NKCC2) in the apical epithelial cell membrane and Na + /K + -ATPase and chloride channel ClC-Kb in the basolateral membrane. K + is circulated via NKCC2 and the renal outer medullary K + channel ROMK1, across the apical cell membrane. These transport processes generate a lumen-positive transepithelial potential that drives additional paracellular reabsorption of Na + as well as the reabsorption of divalent cations, mainly Ca 2+ and Mg 2+ . Paracellular transport is regulated by the tight junction (TJ) in a size-, charge-, and water-selective manner. The main functional constituent of the TJ is the family of claudins with 27 members in mammals. Claudins consist of a four-transmembrane helix bundle, two extracellular segments that expand into the paracellular cleft, and intracellular N and C termini. Claudins interact in cis (within the same plasma membrane) and in trans (with claudins in the plasma membrane of neighbori...

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 92%

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Milatz

Himmerkus

Wulfmeyer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

181

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“…The relationship of this to health and disease was initially shown by genetic linkage of para-cellin-1, or claudin-16, to the autosomal recessive disease of renal hypomagnesemia with hypercalciuria and nephrocalcinosis (Simon et al 1999). The divalent cation channel formed by claudin-16 (Gong et al 2015) is essential for reabsorption of magnesium and calcium ions from the urinary space. Human claudin polymorphisms have also been linked to biliary disease (Hadj-Rabia et al 2004) and deafness (Wilcox et al 2001).…”

Section: Tight Junction Molecular Architecturementioning

confidence: 99%

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Buckley

Turner

2017

Cold Spring Harb Perspect Biol

535

370

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Mucosal surfaces are lined by epithelial cells. In the intestine, the epithelium establishes a selectively permeable barrier that supports nutrient absorption and waste secretion while preventing intrusion by luminal materials. Intestinal epithelia therefore play a central role in regulating interactions between the mucosal immune system and luminal contents, which include dietary antigens, a diverse intestinal microbiome, and pathogens. The paracellular space is sealed by the tight junction, which is maintained by a complex network of protein interactions. Tight junction dysfunction has been linked to a variety of local and systemic diseases. Two molecularly and biophysically distinct pathways across the intestinal tight junction are selectively and differentially regulated by inflammatory stimuli. This review discusses the mechanisms underlying these events, their impact on disease, and the potential of using these as paradigms for development of tight junction-targeted therapeutic interventions.

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“…More importantly, claudin-16 and -19 physically interact (42), and loss of one claudin from the tight junction can cause the other to be endocytosed from the plasma membrane (41). In both mammalian and insect cell membranes, recombinant claudin-16 and -19 proteins form a stable cis -dimer (27). Co-expression of claudin-16 and -19 into polarized epithelial cells can confer significant cation selectivity (P Na /P Cl ) to the tight junction (27, 42).…”

Section: Thick Ascending Limb Of Henle’s Loopmentioning

confidence: 99%

Claudins in barrier and transport function—the kidney

Gong

Hou

2016

Pflugers Arch - Eur J Physiol

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Summary Claudins are discovered to be key players in renal epithelial physiology. They are involved in developmental, physiological and pathophysiological differentiation. In the glomerular podocytes, claudin-1 is an important determinant of cell junction fate. In the proximal tubule, claudin-2 plays important roles in paracellular salt reabsorption. In the thick ascending limb, claudin-14, -16 and -19 regulate the paracellular reabsorption of calcium and magnesium. Recessive mutations in claudin-16 or -19 cause an inherited calcium and magnesium losing disease. Synonymous variants in claudin-14 have been associated with hypercalciuric nephrolithiasis by genome wide association studies (GWAS). More importantly, claudin-14 gene expression can be regulated by extracellular calcium levels via the calcium sensing receptor. In the distal tubules, claudin-4 and -8 form paracellular chloride pathway to facilitate electrogenic sodium reabsorption. Aldosterone, WNK4, Cap1 and KLHL3 are powerful regulators of claudin and the paracellular chloride permeability. The lessons learned on claudins from the kidney will have a broader impact on tight junction biology in other epithelia and endothelia.

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Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization

Abstract: Comprehensive biochemical, biophysical, genetic, and electron microscopic analyses of claudin-16 and -19 interactions show how claudin interaction can influence tight junction permeability and tight junction architecture.

Cited by 60 publications

References 43 publications

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Claudins in barrier and transport function—the kidney

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Biochemical and biophysical analyses of tight junction permeability made of claudin-16 and claudin-19 dimerization

Abstract: Comprehensive biochemical, biophysical, genetic, and electron microscopic analyses of claudin-16 and -19 interactions show how claudin interaction can influence tight junction permeability and tight junction architecture.

Cited by 60 publications

References 43 publications

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na + and Mg 2+ transport

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na + and Mg 2+ transport

Cell Biology of Tight Junction Barrier Regulation and Mucosal Disease

Claudins in barrier and transport function—the kidney

Contact Info

Product

Resources

About

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport

Mosaic expression of claudins in thick ascending limbs of Henle results in spatial separation of paracellular Na ⁺ and Mg ²⁺ transport