Pasteurella multocida Toxin-induced Pim-1 expression disrupts suppressor of cytokine signalling (SOCS)-1 activity

Abstract

SummaryPasteurella 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 anchorageindependent 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.

Pasteurella multocida: from Zoonosis to Cellular Microbiology

“…Recent studies have revealed that in addition to the ␣ subunit of the heterotrimeric G q protein (488)(489)(490), PMT also acts on other G proteins, i.e., G 11 , G i , and G 12/13 (488)(489)(490)(491)(492)(493)(494). A number of studies have implicated PMT as a modulator of host immunity (475,(495)(496)(497)(498) and cellular differentiation and proliferation (476,477,485,(499)(500)(501)(502)(503)(504)(505)(506)(507). Interestingly, because of its potent mitogenic and proliferative properties, there has been speculation that exposure to PMT might play a role in cancer predisposition as a longterm consequence of infection with toxinogenic P. multocida (485,495,499,504,505,(508)(509)(510).…”

TLR8 Couples SOCS-1 and Restrains TLR7-Mediated Antiviral Immunity, Exacerbating West Nile Virus Infection in Mice

“…Since Tlr8 −/− mice had a hyperactive IFN response and reduced Socs-1 , we hypothesized that TLR8 signaling may regulate Socs-1 expression. It has been reported that TLR7/8 signaling induces the expression of Socs-1 in HEK293 cells, yet these studies did not rule out if this signaling is dependent on TLR7 or TLR8 alone, or an effect of combined TLR7 and TLR8 ligation (91). In our report, we demonstrated that SOCS-1 partnered with TLR8, but not TLR7, suggesting SOCS-1 utilizes TLR8 as an adaptor molecule for its regulation.…”

Pasteurella multocida toxin

“…The PMT-dependent stimulation of Akt was attributed to the PMT-mediated release of Gβγ and subsequent Gβγ activation of PI3K [123]. On the other hand, signal transducer and activator of transcription (STAT) signaling pathways are known to regulate expression of Pim kinases [189], and it was shown that PMT stimulates the prolonged activation of JAK2/STAT3/5 pathways in a Gα q -dependent manner [190,191].…”