Inhibition of Akt/GSK3beta signalling pathway by Legionella pneumophila is involved in induction of T-cell apoptosis.
Legionella pneumophila is the causative agent of human Legionnaires' disease. L. pneumophila has been shown to induce apoptosis of T-cells and this may be important pathologically and clinically. The present study has determined the molecular mechanisms underlying L. pneumophila-induced apoptosis, which were unclear. Wild-type L. pneumophila and flagellin-deficient Legionella, but not L. pneumophila lacking a functional type IV secretion system Dot/Icm, replicated in T-cells. However, apoptosis was efficiently induced in T-cells only by wild-type L. pneumophila, and not flagellin-deficient or Dot/Icm-deficient Legionella. Induction of apoptosis involved activation of the initiator caspase 9 and effector caspase 3. Infection with L. pneumophila inhibited phosphorylation of Akt (also known as protein kinase B) and the Akt substrate GSK3beta (glycogen synthase kinase 3beta), and reduced the levels of beta-catenin, a transcriptional activator regulated by GSK3beta. It also caused the activation of the pro-apoptotic protein Bax and inhibited the expression of the anti-apoptotic protein XIAP (X-linked inhibitor of apoptosis) via inhibition of the Akt pathway. In conclusion, L. pneumophila induces mitochondria-mediated T-cell apoptosis through inhibition of the Akt/GSK3beta signalling pathway.
Takamatsu
Reika
R
Division of Molecular Virology and Oncology, Graduate School of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa 903-0215, Japan.
Takeshima
Eriko
E
Ishikawa
Chie
C
Yamamoto
Kei
K
Teruya
Hiromitsu
H
Heuner
Klaus
K
Higa
Futoshi
F
Fujita
Jiro
J
Mori
Naoki
N
D017209:Apoptosis; D015153:Blotting, Western; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation; D005408:Flagellin; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D019169:Jurkat Cells; D016952:Legionella pneumophila / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000382:microbiology* / Q000473:pathology*
D012333:RNA, Messenger; D005408:Flagellin; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D053453:Caspase 9