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.

S-Nitrosylation of Ascorbate Peroxidase Is Part of Programmed Cell Death Signaling in Tobacco Bright Yellow-2 Cells

“…Some evidence suggests that S-nitrosylation could represent a signal for protein degradation through the ubiquitin-proteasome pathway in animal cells (Kim et al, 2004;Kwak et al, 2010;Dunne et al, 2013). Our data show that cAPX is also promptly ubiquitinated in cells undergoing H 2 O 2 -and HS-induced PCDs (Fig.…”

Bacterial secreted effectors and caspase‐3 interactions

“…The result was prolonged survival for infected cells. S-nitrosylation of caspase-3 was not observed in infected epithelial cells again highlighting the difference in response of differing cell types as regards caspase-3 activation (Dunne et al , 2013). S-nitrosylation is also employed by bacteria to control protein stability and homologous proteins to those in host cells are used to mediate the transfer of S-nitrosyl groups to targeted proteins (Mitchell and Marletta, 2005; Gusarov and Nudler, 2012; Seth et al , 2012).…”

Adherent-invasive Escherichia coli in inflammatory bowel disease

“…In response to AIEC infection, tumour necrosis factor α (TNF-α)35 71 72 and other proinflammatory cytokines73 are released, further enhancing dysbiosis and proliferation of AIEC without inducing host cell death. AIEC are able to exploit host mechanisms of apoptosis by increasing S-nitrosylation and proteasomal degradation of caspase-3 in infected macrophages,74favouring their own intracellular replication through modulation of the ubiquitin proteasome system in infected-IEC,75 76 and through the release of exosomes from infected cells 77. In addition, another AIEC property is induction of autophagic neutrophil cell death 78.…”