Conversion of PtdIns(4,5)P2 into PtdIns(5)P by the S.flexneri effector IpgD reorganizes host cell morphology

Abstract

Phosphoinositides play a central role in the control of several cellular events including actin cytoskeleton organization. Here we show that, upon infection of epithelial cells with the Gram‐negative pathogen Shigella flexneri, the virulence factor IpgD is translocated directly into eukaryotic cells and acts as a potent inositol 4‐phosphatase that specifically dephosphorylates phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] into phosphatidylinositol 5‐monophosphate [PtdIns(5)P] that then accumulates. Transfection experiments indicate that the transformation of PtdIns(4,5)P2 into PtdIns(5)P by IpgD is responsible for dramatic morphological changes of the host cell, leading to a decrease in membrane tether force associated with membrane blebbing and actin filament remodelling. These data provide the molecular basis for a new mechanism employed by a pathogenic bacterium to promote membrane ruffling at the entry site.

Tracking the establishment of local endemic populations of an emergent enteric pathogen

“…We identified four SNPs that became fixed in the Vietnamese S. sonnei population during the first evolutionary bottleneck (two intergenic, one synonymous, and one nonsynonymous in a coding sequence of unknown function) and one SNP, a nonsynonymous change in invasion plasmid gene (ipg)D, which became fixed during the second bottleneck. The ipgD gene encodes an effector protein that plays a role in cellular invasion (13) and impairment of T-cell immune function (14); hence, this nonsynonymous SNP may be under selection. We detected no fixation of plasmid SNPs during the third or fourth bottlenecks.…”

Structural basis for substrate recognition by a unique Legionella phosphoinositide phosphatase

“…Although PI phosphatases have been reported from other bacterial pathogens, such as the PI-4-phosphatases IpgD from Shigella flexneri (14), SigD/SopB from S. typhimurium (16,17), no such enzymes have been reported from Legionella species. Our discovery of a PI phosphatase in L. pneumophila not only establishes an archetypal family of PI phosphatase, but also opens a new avenue toward the understanding of the roles of PI signaling and metabolism in L. pneumophila infection.…”

“…Bacterial pathogens have evolved a variety of mechanisms to subvert PI metabolism in host cells. For examples, Shigella flexneri, the causative agent of human dysentery, modifies PI metabolism in host cells to favor its internalization through the PI-4-phosphatase activity of the virulent factor IpgD (14). Salmonella typhimurium, which is responsible for most food-borne gastroenteritis (15), delivers the PI phosphatase SigD/SopB into the host.…”

The phospholipid code: a key component of dying cell recognition, tumor progression and host–microbe interactions

“…Vibrio parahaemolyticus can secrete the effector protein VPA0450, a phosphoinositide 5-phosphatase that dephosphorylates PI(4,5)P 2 to PI(4)P, into host cells to induce membrane blebbing and rapid cell lysis. 105 Shigella flexneri can introduce the virulence factor IpgD, a phosphoinositide 4-phosphatase that dephosphorylates PI(4,5)P 2 to PI(5)P, into mammalian cells to aid infection by modulating a variety of host cellular processes, including actin filament remodeling to assist invasion 106 ( Figure 2h) as well as PI3K/Akt/mTOR signaling to inhibit apoptosis and enable bacterial colonization within host cells. 107 Similarly, the Salmonella typhimurium effector molecule SigD, a homolog of Shigella flexneri IpgD, also displays phosphoinositide 4-phosphatase activity towards PI (4,5)P 2 and causes membrane blebbing and cell rounding in infected cells.…”