Pasteurella multocida Toxin-induced Pim-1 expression disrupts suppressor of cytokine signalling (SOCS)-1 activity.
Pasteurella multocida Toxin (PMT) is a mitogenic protein toxin that manipulates signal transduction cascades of mammalian host cells and upregulates Janus kinase (JAK) and signal transducers of transcription (STAT) activity. Here we show that in the presence of PMT, increased levels of suppressors of cytokine signalling-1 (SOCS-1) proteins significantly enhance STAT activity. This occurs via PMT-induced expression of the serine/threonine kinase Pim-1 and subsequent threonine phosphorylation of SOCS-1. The ability of SOCS-1 to act as an E3 ubiquitin ligase is regulated by its phosphorylation status. Thus, the tyrosine kinase JAK2 cannot be marked for proteasomal degradation by threonine phosphorylated SOCS-1. Consequently, the expression levels of JAK2 are increased, eventually leading to hyperactivity of JAK2 and its target, the transcription factor STAT3. Eventually this causes increased anchorage-independent cell growth that correlates with the expression levels of SOCS-1. Interestingly, endogenous SOCS-1 production after Toll-like receptor activation also causes STAT3 hyperactivation. Thus we hypothesize that P. multocida Toxin alters host cell signalling using mechanisms that have so far only been known to be employed by oncogenic viral kinases to avoid host immune defence mechanisms.
Hildebrand
Dagmar
D
Department für Infektiologie, Medizinische Mikrobiologie und Hygiene, Im Neuenheimer Feld 324, D-69120 Heidelberg, Germany.
Walker
Patrick
P
Dalpke
Alexander
A
Heeg
Klaus
K
Kubatzky
Katharina F
KF
D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D053614:Janus Kinase 2 / Q000378:metabolism; D016979:Pasteurella multocida / Q000472:pathogenicity*; D010766:Phosphorylation; D051573:Proto-Oncogene Proteins c-pim-1 / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
D001426:Bacterial Proteins; D001427:Bacterial Toxins; C062258:Pasteurella multocida toxin; C108944:SOCS1 protein, human; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D053614:Janus Kinase 2; D051573:Proto-Oncogene Proteins c-pim-1