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Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization

Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macroph...

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Autores principales: Panagi, Ioanna, Jennings, Elliott, Zeng, Jingkun, Günster, Regina A., Stones, Cullum D., Mak, Hazel, Jin, Enkai, Stapels, Daphne A.C., Subari, Nur.Z., Pham, Trung H.M., Brewer, Susan M., Ong, Samantha Y.Q., Monack, Denise M., Helaine, Sophie, Thurston, Teresa L.M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953433/
https://www.ncbi.nlm.nih.gov/pubmed/31862381
http://dx.doi.org/10.1016/j.chom.2019.11.002
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author Panagi, Ioanna
Jennings, Elliott
Zeng, Jingkun
Günster, Regina A.
Stones, Cullum D.
Mak, Hazel
Jin, Enkai
Stapels, Daphne A.C.
Subari, Nur.Z.
Pham, Trung H.M.
Brewer, Susan M.
Ong, Samantha Y.Q.
Monack, Denise M.
Helaine, Sophie
Thurston, Teresa L.M.
author_facet Panagi, Ioanna
Jennings, Elliott
Zeng, Jingkun
Günster, Regina A.
Stones, Cullum D.
Mak, Hazel
Jin, Enkai
Stapels, Daphne A.C.
Subari, Nur.Z.
Pham, Trung H.M.
Brewer, Susan M.
Ong, Samantha Y.Q.
Monack, Denise M.
Helaine, Sophie
Thurston, Teresa L.M.
author_sort Panagi, Ioanna
collection PubMed
description Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment.
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spelling pubmed-69534332020-01-14 Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization Panagi, Ioanna Jennings, Elliott Zeng, Jingkun Günster, Regina A. Stones, Cullum D. Mak, Hazel Jin, Enkai Stapels, Daphne A.C. Subari, Nur.Z. Pham, Trung H.M. Brewer, Susan M. Ong, Samantha Y.Q. Monack, Denise M. Helaine, Sophie Thurston, Teresa L.M. Cell Host Microbe Article Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. In addition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatory transcriptional response in macrophages through its effector protein SteE. However, the target(s) and molecular mechanism of SteE remain unknown. Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. SteE itself is a substrate of GSK3, and phosphorylation of SteE is required for its activity. Remarkably, phosphorylated SteE then forces GSK3 to phosphorylate the non-canonical substrate signal transducer and activator of transcription 3 (STAT3) on tyrosine-705. This results in STAT3 activation, which along with GSK3 is required for SteE-mediated upregulation of the anti-inflammatory M2 macrophage marker interleukin-4Rα (IL-4Rα). Overall, the conversion of GSK3 to a tyrosine-directed kinase represents a tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment. Cell Press 2020-01-08 /pmc/articles/PMC6953433/ /pubmed/31862381 http://dx.doi.org/10.1016/j.chom.2019.11.002 Text en © 2019 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Panagi, Ioanna
Jennings, Elliott
Zeng, Jingkun
Günster, Regina A.
Stones, Cullum D.
Mak, Hazel
Jin, Enkai
Stapels, Daphne A.C.
Subari, Nur.Z.
Pham, Trung H.M.
Brewer, Susan M.
Ong, Samantha Y.Q.
Monack, Denise M.
Helaine, Sophie
Thurston, Teresa L.M.
Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
title Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
title_full Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
title_fullStr Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
title_full_unstemmed Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
title_short Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization
title_sort salmonella effector stee converts the mammalian serine/threonine kinase gsk3 into a tyrosine kinase to direct macrophage polarization
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6953433/
https://www.ncbi.nlm.nih.gov/pubmed/31862381
http://dx.doi.org/10.1016/j.chom.2019.11.002
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