title: Modulation of host cell endocytosis by the type III cytotoxin, Pseudomonas ExoS.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA.
authors.forename: Qing
authors.initials: Q
authors.lastname: Deng
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Barbieri
mesh_terms: 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
chemical_list: 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
references.citation: Traffic. 2008 Mar;9(3):325-37
references.pmid: 18088303
references.citation: Traffic. 2007 Oct;8(10):1331-45
references.pmid: 17714437
references.citation: Biochemistry. 2006 Apr 11;45(14):4664-73
references.pmid: 16584201
references.citation: J Cell Biol. 1994 Nov;127(4):915-34
references.pmid: 7962076
references.citation: Infect Immun. 2003 Sep;71(9):5296-305
references.pmid: 12933877
references.citation: Nature. 1999 Sep 16;401(6750):293-7
references.pmid: 10499590
references.citation: J Biol Chem. 2005 Oct 28;280(43):35953-60
references.pmid: 16123042
references.citation: Infect Immun. 1989 Mar;57(3):996-8
references.pmid: 2492977
references.citation: J Biol Chem. 2000 Feb 11;275(6):3745-8
references.pmid: 10660521
references.citation: Exp Cell Res. 2006 Jun 10;312(10):1843-55
references.pmid: 16563376
references.citation: Proc Natl Acad Sci U S A. 1998 Nov 10;95(23):13899-904
references.pmid: 9811898
references.citation: Mol Microbiol. 2000 Aug;37(3):515-27
references.pmid: 10931345
references.citation: Nat Cell Biol. 2002 Sep;4(9):691-8
references.pmid: 12198492
references.citation: Int J Med Microbiol. 2000 Oct;290(4-5):381-7
references.pmid: 11111915
references.citation: Microbiology (Reading). 2001 Oct;147(Pt 10):2659-2669
references.pmid: 11577145
references.citation: Mol Microbiol. 1999 Apr;32(2):393-401
references.pmid: 10231494
references.citation: Mol Microbiol. 1997 Sep;25(6):1125-39
references.pmid: 9350868
references.citation: J Biol Chem. 2004 Sep 10;279(37):38402-8
references.pmid: 15252013
references.citation: Biochem Biophys Res Commun. 2002 Feb 15;291(1):91-100
references.pmid: 11829467
references.citation: Mol Biol Cell. 1998 May;9(5):1107-22
references.pmid: 9571243
references.citation: J Cell Sci. 2006 Jun 15;119(Pt 12):2414-24
references.pmid: 16720641
references.citation: Clin Infect Dis. 1994 Jun;18(6):886-95
references.pmid: 8086548
references.citation: EMBO J. 2003 Jun 16;22(12):2959-69
references.pmid: 12805211
references.citation: Nat Cell Biol. 2005 Jun;7(6):548-50
references.pmid: 15928700
references.citation: J Biol Chem. 1993 Nov 15;268(32):24475-80
references.pmid: 8226999
references.citation: J Biol Chem. 2002 Dec 20;277(51):49158-66
references.pmid: 12364336
references.citation: J Biol Chem. 2007 Apr 27;282(17):13022-32
references.pmid: 17311921
references.citation: Exp Cell Res. 2004 Apr 1;294(2):509-22
references.pmid: 15023538
references.citation: J Cell Sci. 2003 Dec 1;116(Pt 23):4799-810
references.pmid: 14600265
references.citation: Infect Immun. 1991 Nov;59(11):4259-62
references.pmid: 1937783
references.citation: J Neurosci. 2004 Apr 21;24(16):4070-81
references.pmid: 15102922
references.citation: EMBO Rep. 2001 Jan;2(1):68-74
references.pmid: 11252727
references.citation: J Biol Chem. 1996 Nov 29;271(48):30340-6
references.pmid: 8939994
references.citation: Nature. 2000 Nov 16;408(6810):374-7
references.pmid: 11099046
references.citation: J Leukoc Biol. 2000 Nov;68(5):627-32
references.pmid: 11073100
references.citation: Infect Immun. 2000 Dec;68(12):7100-13
references.pmid: 11083836
references.citation: Curr Biol. 1998 Jan 1;8(1):34-45
references.pmid: 9427626
references.citation: J Biol Chem. 2006 Jan 13;281(2):1099-106
references.pmid: 16282324
references.citation: Nat Cell Biol. 2005 Jun;7(6):559-69
references.pmid: 15895077
references.citation: Infect Immun. 2001 Sep;69(9):5329-34
references.pmid: 11500402
references.citation: J Cell Biochem. 1982;19(4):383-94
references.pmid: 6298257
references.citation: J Biol Chem. 2003 Aug 29;278(35):32794-800
references.pmid: 12807879
references.citation: Cell. 1992 Sep 4;70(5):715-28
references.pmid: 1516130
references.citation: Mol Microbiol. 1998 Nov;30(4):751-9
references.pmid: 10094623
references.citation: J Cell Biol. 2000 Oct 30;151(3):539-50
references.pmid: 11062256
references.citation: Science. 1986 Sep 5;233(4768):1061-8
references.pmid: 3090687
references.citation: Exp Cell Res. 2003 Mar 10;284(1):31-53
references.pmid: 12648464
references.citation: Bioessays. 1993 Jun;15(6):375-82
references.pmid: 8395172
references.citation: J Bacteriol. 1997 Nov;179(22):7165-8
references.pmid: 9371466