title: Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive Escherichia coli (AIEC) in immune cells.
abstract: Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients.
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Karl A
authors.initials: KA
authors.lastname: Dunne
authors.forename: Amr
authors.initials: A
authors.lastname: Allam
authors.forename: Anne
authors.initials: A
authors.lastname: McIntosh
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Houston
authors.forename: Vuk
authors.initials: V
authors.lastname: Cerovic
authors.forename: Carl S
authors.initials: CS
authors.lastname: Goodyear
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Roe
authors.forename: Scott A
authors.initials: SA
authors.lastname: Beatson
authors.forename: Simon W
authors.initials: SW
authors.lastname: Milling
authors.forename: Daniel
authors.initials: D
authors.lastname: Walker
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Wall
mesh_terms: D000818:Animals; D001422:Bacterial Adhesion; D053148:Caspase 3 / Q000378:metabolism*; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D004926:Escherichia coli / Q000378:metabolism* / Q000472:pathogenicity; D006801:Humans; D007413:Intestinal Mucosa / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D008264:Macrophages / Q000166:cytology / Q000378:metabolism* / Q000382:microbiology; D009603:Nitroso Compounds / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis
chemical_list: D009603:Nitroso Compounds; D053148:Caspase 3; D046988:Proteasome Endopeptidase Complex