PtdIns5P activates the host cell PI3-kinase/Akt pathway during Shigella flexneri infection.
The virulence factor IpgD, delivered into nonphagocytic cells by the type III secretion system of the pathogen Shigella flexneri, is a phosphoinositide 4-phosphatase generating phosphatidylinositol 5 monophosphate (PtdIns5P). We show that PtdIns5P is rapidly produced and concentrated at the entry foci of the bacteria, where it colocalises with phosphorylated Akt during the first steps of infection. Moreover, S. flexneri-induced phosphorylation of host cell Akt and its targets specifically requires IpgD. Ectopic expression of IpgD in various cell types, but not of its inactive mutant, or addition of short-chain penetrating PtdIns5P is sufficient to induce Akt phosphorylation. Conversely, sequestration of PtdIns5P or reduction of its level strongly decreases Akt phosphorylation in infected cells or in IpgD-expressing cells. Accordingly, IpgD and PtdIns5P production specifically activates a class IA PI 3-kinase via a mechanism involving tyrosine phosphorylations. Thus, S. flexneri parasitism is shedding light onto a new mechanism of PI 3-kinase/Akt activation via PtdIns5P production that plays an important role in host cell responses such as survival.
INSERM Unité 563, CPTP, Département d'Oncogenèse et Signalisation dans les Cellules Hématopoiétiques, Hôpital Purpan, Toulouse, France.
Caroline
C
Pendaries
Hélène
H
Tronchère
Laurence
L
Arbibe
Joelle
J
Mounier
Or
O
Gozani
Lewis
L
Cantley
Michael J
MJ
Fry
Frédérique
F
Gaits-Iacovoni
Philippe J
PJ
Sansonetti
Bernard
B
Payrastre
D000818:Animals; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012763:Shigella flexneri / Q000472:pathogenicity*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D014774:Virulence
D001426:Bacterial Proteins; D018129:Phosphatidylinositol Phosphates; C113567:phosphatidylinositol 5-phosphate; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C425774:IpgD protein, Shigella flexneri; D010744:Phosphoric Monoester Hydrolases