Modulation of host cell endocytosis by the type III cytotoxin, Pseudomonas ExoS.
Pseudomonas aeruginosa ExoS is a bifunctional type III cytotoxin that possesses Rho GTPase-activating protein (RhoGAP) and ADP-ribosyltransferase (ADPr) activities. In the current study, the RhoGAP and ADPr activities of ExoS were tested for the ability to disrupt mammalian epithelial cell physiology. RhoGAP, but not ADPr, inhibited internalization/phagocytosis of bacteria, while ADPr, but not RhoGAP, inhibited vesicle trafficking, both general fluid-phase uptake and EGF-activated EGF receptor (EGFR) degradation. In ADPr-intoxicated cells, upon EGF activation, EGFR co-localized with clathrin-coated vesicles (CCV), which did not mature into Rab5-positive early endosomes. Constitutively, active Rab5 recruited EGFR from CCV to early endosomes. Consistent with the inhibition of Rab5 function by ADPr, several Rab proteins including Rab5 and 9, but not Rab4, were ADP ribosylated by ExoS. Thus, the two enzymatic activities of ExoS have different effects on epithelial cells with RhoGAP inhibiting bacterial internalization and ADPr interfering with CCV maturation. The ability ADPr to inhibit mammalian vesicle trafficking provides a new mechanism for bacterial toxin-mediated virulence.
Deng
Qing
Q
Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
Barbieri
Joseph T
JT
D036002:ADP Ribose Transferases / Q000494:pharmacology*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D001427:Bacterial Toxins / Q000494:pharmacology*; D004705:Endocytosis / Q000187:drug effects*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000502:physiology*; D020696:rab5 GTP-Binding Proteins / Q000037:antagonists & inhibitors
D001427:Bacterial Toxins; D000246:Adenosine Diphosphate Ribose; D004815:Epidermal Growth Factor; D036002:ADP Ribose Transferases; C444820:exoenzyme S; D066246:ErbB Receptors; D020696:rab5 GTP-Binding Proteins
Traffic. 2008 Mar;9(3):325-37
18088303
Traffic. 2007 Oct;8(10):1331-45
17714437
Biochemistry. 2006 Apr 11;45(14):4664-73
16584201
J Cell Biol. 1994 Nov;127(4):915-34
7962076
Infect Immun. 2003 Sep;71(9):5296-305
12933877
Nature. 1999 Sep 16;401(6750):293-7
10499590
J Biol Chem. 2005 Oct 28;280(43):35953-60
16123042
Infect Immun. 1989 Mar;57(3):996-8
2492977
J Biol Chem. 2000 Feb 11;275(6):3745-8
10660521
Exp Cell Res. 2006 Jun 10;312(10):1843-55
16563376
Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13899-904
9811898
Mol Microbiol. 2000 Aug;37(3):515-27
10931345
Nat Cell Biol. 2002 Sep;4(9):691-8
12198492
Int J Med Microbiol. 2000 Oct;290(4-5):381-7
11111915
Microbiology (Reading). 2001 Oct;147(Pt 10):2659-2669
11577145
Mol Microbiol. 1999 Apr;32(2):393-401
10231494
Mol Microbiol. 1997 Sep;25(6):1125-39
9350868
J Biol Chem. 2004 Sep 10;279(37):38402-8
15252013
Biochem Biophys Res Commun. 2002 Feb 15;291(1):91-100
11829467
Mol Biol Cell. 1998 May;9(5):1107-22
9571243
J Cell Sci. 2006 Jun 15;119(Pt 12):2414-24
16720641
Clin Infect Dis. 1994 Jun;18(6):886-95
8086548
EMBO J. 2003 Jun 16;22(12):2959-69
12805211
Nat Cell Biol. 2005 Jun;7(6):548-50
15928700
J Biol Chem. 1993 Nov 15;268(32):24475-80
8226999
J Biol Chem. 2002 Dec 20;277(51):49158-66
12364336
J Biol Chem. 2007 Apr 27;282(17):13022-32
17311921
Exp Cell Res. 2004 Apr 1;294(2):509-22
15023538
J Cell Sci. 2003 Dec 1;116(Pt 23):4799-810
14600265
Infect Immun. 1991 Nov;59(11):4259-62
1937783
J Neurosci. 2004 Apr 21;24(16):4070-81
15102922
EMBO Rep. 2001 Jan;2(1):68-74
11252727
J Biol Chem. 1996 Nov 29;271(48):30340-6
8939994
Nature. 2000 Nov 16;408(6810):374-7
11099046
J Leukoc Biol. 2000 Nov;68(5):627-32
11073100
Infect Immun. 2000 Dec;68(12):7100-13
11083836
Curr Biol. 1998 Jan 1;8(1):34-45
9427626
J Biol Chem. 2006 Jan 13;281(2):1099-106
16282324
Nat Cell Biol. 2005 Jun;7(6):559-69
15895077
Infect Immun. 2001 Sep;69(9):5329-34
11500402
J Cell Biochem. 1982;19(4):383-94
6298257
J Biol Chem. 2003 Aug 29;278(35):32794-800
12807879
Cell. 1992 Sep 4;70(5):715-28
1516130
Mol Microbiol. 1998 Nov;30(4):751-9
10094623
J Cell Biol. 2000 Oct 30;151(3):539-50
11062256
Science. 1986 Sep 5;233(4768):1061-8
3090687
Exp Cell Res. 2003 Mar 10;284(1):31-53
12648464
Bioessays. 1993 Jun;15(6):375-82
8395172
J Bacteriol. 1997 Nov;179(22):7165-8
9371466