Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis.
The 146-kDa Pasteurella multocida toxin (PMT) is the main virulence factor to induce P. multocida-associated progressive atrophic rhinitis in various animals. PMT leads to a destruction of nasal turbinate bones implicating an effect of the toxin on osteoblasts and/or osteoclasts. The toxin induces c...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC3656108?pdf=render |
| _version_ | 1811205138363187200 |
|---|---|
| author | Peter Siegert Gudula Schmidt Panagiotis Papatheodorou Thomas Wieland Klaus Aktories Joachim H C Orth |
| author_facet | Peter Siegert Gudula Schmidt Panagiotis Papatheodorou Thomas Wieland Klaus Aktories Joachim H C Orth |
| author_sort | Peter Siegert |
| collection | DOAJ |
| description | The 146-kDa Pasteurella multocida toxin (PMT) is the main virulence factor to induce P. multocida-associated progressive atrophic rhinitis in various animals. PMT leads to a destruction of nasal turbinate bones implicating an effect of the toxin on osteoblasts and/or osteoclasts. The toxin induces constitutive activation of Gα proteins of the G(q/11)-, G₁₂/₁₃- and G(i)-family by deamidating an essential glutamine residue. To study the PMT effect on bone cells, we used primary osteoblasts derived from rat calvariae and stromal ST-2 cells as differentiation model. As marker of functional osteoblasts the expression and activity of alkaline phosphatase, formation of mineralization nodules or expression of specific transcription factors as osterix was determined. Here, we show that the toxin inhibits differentiation and/or function of osteoblasts by activation of Gα(q/11). Subsequently, Gα(q/11) activates RhoA via p63RhoGEF, which specifically interacts with Gα(q/11) but not with other G proteins like Gα₁₂/₁₃ and Gα(i). Activated RhoA transactivates the mitogen-activated protein (MAP) kinase cascade via Rho kinase, involving Ras, MEK and ERK, resulting in inhibition of osteoblast differentiation. PMT-induced inhibition of differentiation was selective for the osteoblast lineage as adipocyte-like differentiation of ST-2 cells was not hampered. The present work provides novel insights, how the bacterial toxin PMT can control osteoblastic development by activating heterotrimeric G proteins of the Gα(q/11)-family and is a molecular pathogenetic basis for understanding the role of the toxin in bone loss during progressive atrophic rhinitis induced by Pasteurella multocida. |
| first_indexed | 2024-04-12T03:25:32Z |
| format | Article |
| id | doaj.art-db01ae9eb9c747588c3238dd174d33f1 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-04-12T03:25:32Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-db01ae9eb9c747588c3238dd174d33f12022-12-22T03:49:44ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-01-0195e100338510.1371/journal.ppat.1003385Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis.Peter SiegertGudula SchmidtPanagiotis PapatheodorouThomas WielandKlaus AktoriesJoachim H C OrthThe 146-kDa Pasteurella multocida toxin (PMT) is the main virulence factor to induce P. multocida-associated progressive atrophic rhinitis in various animals. PMT leads to a destruction of nasal turbinate bones implicating an effect of the toxin on osteoblasts and/or osteoclasts. The toxin induces constitutive activation of Gα proteins of the G(q/11)-, G₁₂/₁₃- and G(i)-family by deamidating an essential glutamine residue. To study the PMT effect on bone cells, we used primary osteoblasts derived from rat calvariae and stromal ST-2 cells as differentiation model. As marker of functional osteoblasts the expression and activity of alkaline phosphatase, formation of mineralization nodules or expression of specific transcription factors as osterix was determined. Here, we show that the toxin inhibits differentiation and/or function of osteoblasts by activation of Gα(q/11). Subsequently, Gα(q/11) activates RhoA via p63RhoGEF, which specifically interacts with Gα(q/11) but not with other G proteins like Gα₁₂/₁₃ and Gα(i). Activated RhoA transactivates the mitogen-activated protein (MAP) kinase cascade via Rho kinase, involving Ras, MEK and ERK, resulting in inhibition of osteoblast differentiation. PMT-induced inhibition of differentiation was selective for the osteoblast lineage as adipocyte-like differentiation of ST-2 cells was not hampered. The present work provides novel insights, how the bacterial toxin PMT can control osteoblastic development by activating heterotrimeric G proteins of the Gα(q/11)-family and is a molecular pathogenetic basis for understanding the role of the toxin in bone loss during progressive atrophic rhinitis induced by Pasteurella multocida.http://europepmc.org/articles/PMC3656108?pdf=render |
| spellingShingle | Peter Siegert Gudula Schmidt Panagiotis Papatheodorou Thomas Wieland Klaus Aktories Joachim H C Orth Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis. PLoS Pathogens |
| title | Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis. |
| title_full | Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis. |
| title_fullStr | Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis. |
| title_full_unstemmed | Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis. |
| title_short | Pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the MAP-kinase cascade via the Gα(q/11)--p63RhoGEF--RhoA axis. |
| title_sort | pasteurella multocida toxin prevents osteoblast differentiation by transactivation of the map kinase cascade via the gα q 11 p63rhogef rhoa axis |
| url | http://europepmc.org/articles/PMC3656108?pdf=render |
| work_keys_str_mv | AT petersiegert pasteurellamultocidatoxinpreventsosteoblastdifferentiationbytransactivationofthemapkinasecascadeviathegaq11p63rhogefrhoaaxis AT gudulaschmidt pasteurellamultocidatoxinpreventsosteoblastdifferentiationbytransactivationofthemapkinasecascadeviathegaq11p63rhogefrhoaaxis AT panagiotispapatheodorou pasteurellamultocidatoxinpreventsosteoblastdifferentiationbytransactivationofthemapkinasecascadeviathegaq11p63rhogefrhoaaxis AT thomaswieland pasteurellamultocidatoxinpreventsosteoblastdifferentiationbytransactivationofthemapkinasecascadeviathegaq11p63rhogefrhoaaxis AT klausaktories pasteurellamultocidatoxinpreventsosteoblastdifferentiationbytransactivationofthemapkinasecascadeviathegaq11p63rhogefrhoaaxis AT joachimhcorth pasteurellamultocidatoxinpreventsosteoblastdifferentiationbytransactivationofthemapkinasecascadeviathegaq11p63rhogefrhoaaxis |