Claudin-16 and claudin-19 interaction is required for their assembly into tight junctions and for renal reabsorption of magnesium.
Claudins are tight junction integral membrane proteins that are key regulators of the paracellular pathway. Defects in claudin-16 (CLDN16) and CLDN19 function result in the inherited human renal disorder familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC). Previous studies showed that siRNA knockdown of CLDN16 in mice results in a mouse model for FHHNC. Here, we show that CLDN19-siRNA mice also developed the FHHNC symptoms of chronic renal wasting of magnesium and calcium together with defective renal salt handling. siRNA knockdown of CLDN19 caused a loss of CLDN16 from tight junctions in the thick ascending limb (TAL) without a decrease in CLDN16 expression level, whereas siRNA knockdown of CLDN16 produced a similar effect on CLDN19. In both mouse lines, CLDN10, CLDN18, occludin, and ZO-1, normal constituents of TAL tight junctions, remained correctly localized. CLDN16- and CLDN19-depleted tight junctions had normal barrier function but defective ion selectivity. These data, together with yeast two-hybrid binding studies, indicate that a heteromeric CLDN16 and CLDN19 interaction was required for assembling them into the tight junction structure and generating cation-selective paracellular channels.
Hou
Jianghui
J
Department of Cell Biology, Harvard Medical School, 240 Longwood Avenue, Boston, MA 02115, USA. jhou@dom.wustl.edu
Renigunta
Aparna
A
Gomes
Antonio S
AS
Hou
Mingli
M
Paul
David L
DL
Waldegger
Siegfried
S
Goodenough
Daniel A
DA
D000042:Absorption; D000818:Animals; D057167:Claudins; D003001:Cloning, Molecular; D015151:Immunoblotting; D016086:Lentivirus; D008138:Loop of Henle / Q000378:metabolism*; D008274:Magnesium / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009841:Oligonucleotides / Q000235:genetics; D019108:Tight Junctions / Q000378:metabolism*
D057167:Claudins; C502666:Cldn19 protein, mouse; D008565:Membrane Proteins; D009841:Oligonucleotides; C502010:claudin 16; D008274:Magnesium
Nat Rev Mol Cell Biol. 2001 Apr;2(4):285-93
11283726
Cell Mol Life Sci. 2006 Feb;63(4):505-14
16456617
J Cell Biol. 1994 Dec;127(6 Pt 1):1617-26
7798316
Mol Cell Biol. 2001 Nov;21(21):7380-90
11585919
FASEB J. 2008 Jan;22(1):146-58
17761522
J Cell Sci. 2005 Nov 1;118(Pt 21):5109-18
16234325
J Am Soc Nephrol. 2002 Apr;13(4):875-886
11912246
Am J Hum Genet. 2006 Nov;79(5):949-57
17033971
J Cell Biol. 1999 Dec 27;147(7):1569-82
10613913
Am J Physiol Renal Physiol. 2003 Dec;285(6):F1078-84
13129853
Annu Rev Cell Biol. 1989;5:277-307
2688707
Protein Sci. 2003 Feb;12(2):218-27
12538885
Am J Physiol Cell Physiol. 2003 Jun;284(6):C1346-54
12700140
Nat Cell Biol. 2000 Aug;2(8):531-9
10934474
Proc Natl Acad Sci U S A. 1999 Jan 19;96(2):511-6
9892664
Am J Physiol Renal Physiol. 2006 Dec;291(6):F1288-99
16804102
Int Rev Cytol. 1974;39:191-283
4611943
J Clin Invest. 2008 Feb;118(2):619-28
18188451
J Cell Biol. 1986 Sep;103(3):755-66
3528172
Cell. 2006 Aug 25;126(4):741-54
16923393
J Biol Chem. 2007 Jun 8;282(23):17114-22
17442678
J Cell Biol. 1970 May;45(2):272-90
4105112
J Cell Biol. 1999 Dec 13;147(6):1351-63
10601346
Nat Cell Biol. 2005 Mar;7(3):262-9
15723052
Science. 1999 Jul 2;285(5424):103-6
10390358
In Vitro Cell Dev Biol. 1991 May;27A(5):409-16
1649164
J Biol Chem. 2000 Jul 7;275(27):20520-6
10877843
Am J Physiol Renal Physiol. 2008 Dec;295(6):F1641-7
18784260
Cell. 1993 Sep 24;74(6):1065-77
7691412