Modulation and Utilization of Host Cell Phosphoinositides by Salmonella spp

Abstract

Interactions between microbial pathogens and their hosts can be extremely complex. A good example is the facultative intracellular pathogen Salmonella enterica, which causes typhoid fever and gastroenteritis in humans. In order to subvert host cell functions, Salmonella uses type III secretion systems (TTSSs) to translocate effector proteins directly into the host cell. Salmonella pathogenicity island 1 (SPI1) and SPI2 encode two TTSSs that are required for invasion and intracellular survival, respectively. Although the functions of most TTSS effector proteins have yet to be elucidated, it is clear that these proteins affect a diverse set of eukaryotic processes. Research has predominantly concentrated on identifying the host protein targets of Salmonella effectors; however, there is now significant evidence that phosphoinositide signaling pathways are also targeted. The implications of this possibility are considerable since it dramatically increases the number of processes that can be modulated by the pathogen. PHOSPHOINOSITIDESPhosphoinositides are the phosphorylated products of phosphatidylinositol, which consists of a myo-inositol headgroup connected to a diacylglycerol (DAG) via a phosphodiester linkage (Fig. 1). The free hydroxyl groups at positions 3, 4, and 5 of the inositol ring can be phosphorylated in different combinations, yielding seven different phosphoinositides that are essential components of cellular signaling pathways. Together, these molecules regulate the basic processes which determine cell function and activity, including cell growth and differentiation, actin assembly, cell motility, cell death, membrane trafficking, and glucose transport (9, 21, 49, 58). Even though phosphoinositides are minor membrane lipids, their synthesis and degradation must be exquisitely controlled, both spatially and temporally, and there is an almost bewildering array of lipid kinases, phosphatases, and phospholipases (49).In essence, phosphoinositides initiate cellular processes by recruiting proteins from the cytosol to specific membrane localizations. Proteins that interact with phosphoinositides contain recognition domains, such as the FYVE, PH (pleckstrin homology), and PX (phox homology) domains (26), that associate with various degrees of affinity and specificity with particular phosphoinositides. It should be emphasized that phosphoinositides also act as precursors for soluble inositol polyphosphates and DAG, which are important second messengers. For example, hydrolysis of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P 2 (PIP2)] by phospholipase C yields inositol 1,4,5-triphosphate [Ins(1,4,5)P 3 ], which mediates intracellular calcium release, and DAG, which can activate protein kinase C (1). Given the essential and all-encompassing nature of these processes in cell biology, it is not surprising that phosphoinositides also play vital roles in pathogen-host cell interactions. In this minireview we summarize recent data pertaining to the involvement of phosphoinositides in Salmonella invasion, vacuole...

Role for Myosin II in Regulating Positioning ofSalmonella-Containing Vacuoles and Intracellular Replication

“…However, the in vivo substrates of SopB remain unclear (18), and it is not known how its phosphatase activity mediates Rho family GTPase activation. Data presented here suggest that SopB activates myosin II locally through a Rho/ROCK/ MLC signaling pathway that leads to correct SCV positioning.…”

The amino-terminal non-catalytic region of Salmonella typhimurium SigD affects actin organization in yeast and mammalian cells

“…The Salmonella SigD protein, like its homologue IpgD from Shigella , bears domains conserved within the inositol 4‐phosphatase and 5‐phosphatase families in its C‐terminal region, and is known to act both in vivo and in vitro as a phosphatidylinositol and inositol polyphosphate phosphatase (Norris et al ., 1998; Feng et al ., 2001; Marcus et al ., 2001; Niebuhr et al ., 2002; see also Drecktrah et al ., 2004; Terebiznik et al ., 2002 for reviews). All evidence in literature points towards a key role of its enzymatic activity in virulence: (i) expression of SigD in cell lines causes soluble inositol phosphate fluxes (Feng et al ., 2001); (ii) activation of cellular Akt/PKB, which occurs in Salmonella ‐infected cells, depends on the integrity of the catalytic domain of SigD (Steele‐Mortimer et al ., 2000; Marcus et al ., 2001); and (iii) proper formation and maturation of endocytic vesicles during the invasive process requires hydrolysis of PtdIns 4,5–P 2 and PtdIns 3,5–P 2 respectively, by SigD (Terebiznik et al ., 2002; Hernandez et al ., 2004).…”

Akt/Protein Kinase B Modulates Macrophage Inflammatory Response toFrancisellaInfection and Confers a Survival Advantage in Mice

“…These data suggest that either phagosomal escape or the expression of one or more of the pathogenicity island genes may specifically regulate Akt activation, perhaps through interference with host cell phosphoinositide signaling. Indeed, previous reports have shown that the intracellular pathogen Salmonella produces the effector protein SigD/SopB, which can hydrolyze phosphoinositides such as PIP 3 (35). It is tempting to speculate that F. novicida may express a similar molecule that can regulate host cell phospholipid metabolism.…”