Coordinated Regulation of Expression ofSalmonellaPathogenicity Island 1 and Flagellar Type III Secretion Systems by ATP-Dependent ClpXP Protease

Abstract

Salmonella enterica serovar Typhimurium delivers a variety of proteins via the Salmonella pathogenicity island 1 (SPI1)-encoded type III secretion system into host cells, where they elicit several physiological changes, including bacterial invasion, macrophage apoptosis, and enteropathogenesis. Once Salmonella has established a systemic infection, excess macrophage apoptosis would be detrimental to the pathogen, as it utilizes macrophages as vectors for systemic dissemination throughout the host. Therefore, SPI1 expression must be restricted to one or a few specific locations in the host. In the present study, we have demonstrated that the expression of this complex of genes is repressed by the ATP-dependent ClpXP protease, which therefore suppresses macrophage apoptosis. Depletion of ClpXP caused significant increases in the amounts of two SPI1-encoded transcriptional regulators, HilC and HilD, leading to the stimulation of hilA induction and therefore activation of SPI1 expression. Our evidence shows that ClpXP regulates cellular levels of HilC and HilD via the control of flagellar gene expression. Subsequent experiments demonstrated that the flagellumrelated gene product FliZ controls HilD posttranscriptionally, and this in turn activates HilC. These findings suggest that the ClpXP protease coregulates SPI1-related virulence phenotypes and motility. ClpXP is a member of the stress protein family induced in bacteria exposed to hostile environments such as macrophages.

Regulation ofSalmonella entericaPathogenicity Island 1 by DNA Adenine Methylation

“…The occurrence of Dam-dependent post-transcriptional control of hilD stability fits well in the current view that hilD mRNA may be the target for integration of multiple signals that regulate SPI-1 expression (Lucas and Lee 2001; Ellermeier and Slauch 2008;Kage et al 2008). However, with the potential exception of FliZ (Kage et al 2008) and CsrA (Altier et al 2000;Ellermeier and Slauch 2007), post-transcriptional regulators of hilD seem to affect either the HilD protein level (Takaya et al 2005;Matsui et al 2008) or HilD protein activity (Baxter et al 2003;Ellermeier and Slauch 2008 Figure S4.…”

“…However, with the potential exception of FliZ (Kage et al 2008) and CsrA (Altier et al 2000;Ellermeier and Slauch 2007), post-transcriptional regulators of hilD seem to affect either the HilD protein level (Takaya et al 2005;Matsui et al 2008) or HilD protein activity (Baxter et al 2003;Ellermeier and Slauch 2008 Figure S4.…”

Mathematical model of flagella gene expression dynamics in Salmonella enterica serovar typhimurium

“…This likely implies that post-secretion, FliZ made from the class 3 transcript is responsible for activation of SPI1 and SPI4 gene expression. The role of FliZ in activating SPI1 and SPI4 gene expression has been previously reported (Chubiz et al 2010;Kage et al 2008;Saini and Rao 2010;Saini et al 2010b).…”

“…Second, unlike E. coli, in Salmonella, the flagellar regulon is never truly in the OFF state. And last, in Salmonella, motility is a virulence factor, and proteins from the flagellar network have been shown to regulate genes on Pathogenicity Island of the organism (Chubiz et al 2010;Iyoda et al 2001;Kage et al 2008). To study these questions, we develop a model taking into account all major feedback loops in the network, and study the impact of different interactions on the dynamics of gene expression.…”

The Factors of Salmonella Virulency and Pathogenesis of the Salmonella Infection

“…Спåöèфè÷å-ñêèå ðåöåпòîðы ðàñпîзíàюò ìîëåêóëы, àññîöèèðîâàííыå ñ пàòîгåíàìè, âêëю÷àÿ ëèпîпîëèñàхàðèä (ЛПС) è фëàгåëëèí, è ñâÿзыâàюòñÿ ñ ëèгàíäîì íà пîâåðхíîñòè êëåòêè èëè âíóòðè фàгîñîìы, âîзäåéñòâóÿ òåì ñàìыì íà ñîзðåâàíèå фàгîñîìы, эêñпðåññèю ñèгíàëîâ è гåíîâ [25].  òî âðåìÿ êàê фàгîöèòîз ÿâëÿåòñÿ âàжíåéшåé фóíêöèåé âðîжäåííîгî èììóíèòåòà, ðàññ÷èòàííîé íà пðèìåíåíèå ê ìàêñèìàëüíî шèðîêîìó êðóгó ðàзëè÷íых пàòîгåíîâ, îпîñðåäîâàííàÿ ñèñòåìàìè ñåêðåöèè èíâàзèÿ ñàëüìîíåëë â эпèòåëèàëüíыå êëåòêè � âыñîêî ñпåöèфè÷åñêèé пðîöåññ, êîòîðыé зà-âèñèò îò òî÷íîé ðåгóëÿöèè эêñпðåññèè ðÿäà бàêòåðèàëüíых фàêòîðîâ [22]. изâåñòíы íåñêîëüêî ñèñòåì ñåêðåöèè.…”