Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin.
Botulinum neurotoxin is produced by Clostridium botulinum and forms large protein complexes through associations with nontoxic components. We recently found that hemagglutinin (HA), one of the nontoxic components, disrupts the intercellular epithelial barrier; however, the mechanism underlying this phenomenon is not known. In this study, we identified epithelial cadherin (E-cadherin) as a target molecule for HA. HA directly binds E-cadherin and disrupts E-cadherin-mediated cell to cell adhesion. Although HA binds human, bovine, and mouse E-cadherin, it does not bind rat or chicken E-cadherin homologues. HA does not interact with other members of the classical cadherin family such as neural and vascular endothelial cadherin. Expression of rat E-cadherin but not mouse rescues Madin-Darby canine kidney cells from HA-induced tight junction (TJ) disruptions. These data demonstrate that botulinum HA directly binds E-cadherin and disrupts E-cadherin-mediated cell to cell adhesion in a species-specific manner and that the HA-E-cadherin interaction is essential for the disruption of TJ function.
Sugawara
Yo
Y
Laboratory for Infection Cell Biology, International Research Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Matsumura
Takuhiro
T
Takegahara
Yuki
Y
Jin
Yingji
Y
Tsukasaki
Yoshikazu
Y
Takeichi
Masatoshi
M
Fujinaga
Yukako
Y
D000818:Animals; D001905:Botulinum Toxins / Q000378:metabolism* / Q000494:pharmacology; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006388:Hemagglutinins / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D051379:Mice; D051381:Rats
D015820:Cadherins; D006388:Hemagglutinins; D001905:Botulinum Toxins
Avian Dis. 1980 Jul-Sep;24(3):658-64
7004433
Physiol Rev. 2000 Apr;80(2):717-66
10747206
Science. 2001 Jun 1;292(5522):1722-5
11387478
Infect Immun. 1977 Jun;16(3):910-4
19355
J Cell Biol. 1993 May;121(3):485-9
8486730
Infect Immun. 2002 May;70(5):2512-8
11953390
J Pharmacol Exp Ther. 1997 Mar;280(3):1489-98
9067339
Nature. 2008 Oct 23;455(7216):1114-8
18806773
J Cell Biol. 1998 Jun 29;141(7):1539-50
9647647
Mech Dev. 1990 Dec;33(1):49-56
1710917
Cold Spring Harb Perspect Biol. 2009 Sep;1(3):a003053
20066110
J Cell Biol. 1963 May;17:375-412
13944428
EMBO J. 2004 Apr 21;23(8):1699-708
15071499
Science. 1989 Aug 11;245(4918):631-5
2762814
EMBO J. 1989 Jun;8(6):1711-7
2788574
Infect Immun. 1977 Apr;16(1):107-9
326664
Mol Pharmacol. 2005 Mar;67(3):749-56
15602007
J Cell Biol. 1994 Oct;127(1):247-56
7929567
PLoS Biol. 2007 Mar;5(3):e64
17311474
Nat Immunol. 2001 Nov;2(11):1004-9
11685223
Pharmacol Ther. 1982;19(2):165-94
6763707
Dev Biol. 1984 Jan;101(1):19-27
6692973
Avian Dis. 1971 Oct-Dec;15(4):716-22
4945990
J Cell Biol. 1988 Oct;107(4):1575-87
3049625
J Cell Biol. 1999 Oct 4;147(1):195-204
10508866
Cell Microbiol. 2008 Feb;10(2):355-64
17868282
Nat Cell Biol. 2007 Jan;9(1):92-8
17159998
Science. 2002 May 17;296(5571):1308-13
11964443
Infect Immun. 1997 Apr;65(4):1431-9
9119484
J Biol Chem. 1998 Aug 21;273(34):21950-7
9705335
J Cell Biol. 1986 Feb;102(2):457-68
3511070
Genes Dev. 2000 May 15;14(10):1169-80
10817752
Infect Immun. 2007 May;75(5):2126-35
17339363
Histochem Cell Biol. 2008 Feb;129(2):223-32
18034259
JAMA. 2001 Feb 28;285(8):1059-70
11209178
Cell Microbiol. 2008 Feb;10(2):375-87
17900298
EMBO J. 1999 Jul 15;18(14):3956-63
10406800
Annu Rev Pharmacol Toxicol. 2004;44:167-93
14744243
Mol Biol Cell. 2007 Jan;18(1):189-200
17093058
Proc Natl Acad Sci U S A. 1985 May;82(9):2789-93
3857614
J Cell Biol. 1985 Oct;101(4):1307-15
2995405
Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14979-84
9844001
Infect Immun. 2000 Mar;68(3):1441-9
10678958
Transl Res. 2007 Apr;149(4):211-22
17383595
Cell. 1996 Mar 22;84(6):923-32
8601315
Microbiology (Reading). 2009 Jan;155(Pt 1):35-45
19118344
Nature. 1987 Sep 24-30;329(6137):341-3
3498123