Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or...
Ausführliche Beschreibung
Autor*in: |
Jia, Yonggen [verfasserIn] Marq, Jean‐Baptiste [verfasserIn] Bisio, Hugo [verfasserIn] Jacot, Damien [verfasserIn] Mueller, Christina [verfasserIn] Yu, Lu [verfasserIn] Choudhary, Jyoti [verfasserIn] Brochet, Mathieu [verfasserIn] Soldati‐Favre, Dominique [verfasserIn] |
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Format: |
E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
2017 |
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Schlagwörter: |
cAMP‐dependent protein kinase A |
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Anmerkung: |
© The Authors 2017 |
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Übergeordnetes Werk: |
Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 36(2017), 21 vom: 13. Okt., Seite 3250-3267 |
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Übergeordnetes Werk: |
volume:36 ; year:2017 ; number:21 ; day:13 ; month:10 ; pages:3250-3267 |
Links: |
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DOI / URN: |
10.15252/embj.201796794 |
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Katalog-ID: |
SPR058064478 |
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520 | |a Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. | ||
520 | |a Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. | ||
520 | |a Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. | ||
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700 | 1 | |a Marq, Jean‐Baptiste |e verfasserin |4 aut | |
700 | 1 | |a Bisio, Hugo |e verfasserin |4 aut | |
700 | 1 | |a Jacot, Damien |e verfasserin |4 aut | |
700 | 1 | |a Mueller, Christina |e verfasserin |4 aut | |
700 | 1 | |a Yu, Lu |e verfasserin |4 aut | |
700 | 1 | |a Choudhary, Jyoti |e verfasserin |4 aut | |
700 | 1 | |a Brochet, Mathieu |e verfasserin |0 (orcid)0000-0003-3911-5537 |4 aut | |
700 | 1 | |a Soldati‐Favre, Dominique |e verfasserin |0 (orcid)0000-0003-4156-2109 |4 aut | |
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10.15252/embj.201796794 doi (DE-627)SPR058064478 (SPR)embj.201796794-e DE-627 ger DE-627 rakwb eng Jia, Yonggen verfasserin aut Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2017 Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. acylation (dpeaa)DE-He213 cAMP‐dependent protein kinase A (dpeaa)DE-He213 cGMP‐dependent protein kinase G (dpeaa)DE-He213 egress (dpeaa)DE-He213 Marq, Jean‐Baptiste verfasserin aut Bisio, Hugo verfasserin aut Jacot, Damien verfasserin aut Mueller, Christina verfasserin aut Yu, Lu verfasserin aut Choudhary, Jyoti verfasserin aut Brochet, Mathieu verfasserin (orcid)0000-0003-3911-5537 aut Soldati‐Favre, Dominique verfasserin (orcid)0000-0003-4156-2109 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 36(2017), 21 vom: 13. Okt., Seite 3250-3267 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267 https://dx.doi.org/10.15252/embj.201796794 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 36 2017 21 13 10 3250-3267 |
spelling |
10.15252/embj.201796794 doi (DE-627)SPR058064478 (SPR)embj.201796794-e DE-627 ger DE-627 rakwb eng Jia, Yonggen verfasserin aut Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2017 Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. acylation (dpeaa)DE-He213 cAMP‐dependent protein kinase A (dpeaa)DE-He213 cGMP‐dependent protein kinase G (dpeaa)DE-He213 egress (dpeaa)DE-He213 Marq, Jean‐Baptiste verfasserin aut Bisio, Hugo verfasserin aut Jacot, Damien verfasserin aut Mueller, Christina verfasserin aut Yu, Lu verfasserin aut Choudhary, Jyoti verfasserin aut Brochet, Mathieu verfasserin (orcid)0000-0003-3911-5537 aut Soldati‐Favre, Dominique verfasserin (orcid)0000-0003-4156-2109 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 36(2017), 21 vom: 13. Okt., Seite 3250-3267 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267 https://dx.doi.org/10.15252/embj.201796794 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 36 2017 21 13 10 3250-3267 |
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10.15252/embj.201796794 doi (DE-627)SPR058064478 (SPR)embj.201796794-e DE-627 ger DE-627 rakwb eng Jia, Yonggen verfasserin aut Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2017 Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. acylation (dpeaa)DE-He213 cAMP‐dependent protein kinase A (dpeaa)DE-He213 cGMP‐dependent protein kinase G (dpeaa)DE-He213 egress (dpeaa)DE-He213 Marq, Jean‐Baptiste verfasserin aut Bisio, Hugo verfasserin aut Jacot, Damien verfasserin aut Mueller, Christina verfasserin aut Yu, Lu verfasserin aut Choudhary, Jyoti verfasserin aut Brochet, Mathieu verfasserin (orcid)0000-0003-3911-5537 aut Soldati‐Favre, Dominique verfasserin (orcid)0000-0003-4156-2109 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 36(2017), 21 vom: 13. Okt., Seite 3250-3267 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267 https://dx.doi.org/10.15252/embj.201796794 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 36 2017 21 13 10 3250-3267 |
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10.15252/embj.201796794 doi (DE-627)SPR058064478 (SPR)embj.201796794-e DE-627 ger DE-627 rakwb eng Jia, Yonggen verfasserin aut Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2017 Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. acylation (dpeaa)DE-He213 cAMP‐dependent protein kinase A (dpeaa)DE-He213 cGMP‐dependent protein kinase G (dpeaa)DE-He213 egress (dpeaa)DE-He213 Marq, Jean‐Baptiste verfasserin aut Bisio, Hugo verfasserin aut Jacot, Damien verfasserin aut Mueller, Christina verfasserin aut Yu, Lu verfasserin aut Choudhary, Jyoti verfasserin aut Brochet, Mathieu verfasserin (orcid)0000-0003-3911-5537 aut Soldati‐Favre, Dominique verfasserin (orcid)0000-0003-4156-2109 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 36(2017), 21 vom: 13. Okt., Seite 3250-3267 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267 https://dx.doi.org/10.15252/embj.201796794 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 36 2017 21 13 10 3250-3267 |
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10.15252/embj.201796794 doi (DE-627)SPR058064478 (SPR)embj.201796794-e DE-627 ger DE-627 rakwb eng Jia, Yonggen verfasserin aut Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii 2017 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Authors 2017 Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. acylation (dpeaa)DE-He213 cAMP‐dependent protein kinase A (dpeaa)DE-He213 cGMP‐dependent protein kinase G (dpeaa)DE-He213 egress (dpeaa)DE-He213 Marq, Jean‐Baptiste verfasserin aut Bisio, Hugo verfasserin aut Jacot, Damien verfasserin aut Mueller, Christina verfasserin aut Yu, Lu verfasserin aut Choudhary, Jyoti verfasserin aut Brochet, Mathieu verfasserin (orcid)0000-0003-3911-5537 aut Soldati‐Favre, Dominique verfasserin (orcid)0000-0003-4156-2109 aut Enthalten in The EMBO Journal Nature Publishing Group UK, 2023 36(2017), 21 vom: 13. Okt., Seite 3250-3267 (DE-627)266022529 (DE-600)1467419-1 1460-2075 nnns volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267 https://dx.doi.org/10.15252/embj.201796794 X:SPRINGER Resolving-System lizenzpflichtig Volltext SYSFLAG_0 GBV_SPRINGER GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_72 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_120 GBV_ILN_138 GBV_ILN_150 GBV_ILN_151 GBV_ILN_161 GBV_ILN_168 GBV_ILN_170 GBV_ILN_171 GBV_ILN_187 GBV_ILN_211 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_252 GBV_ILN_266 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_636 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2006 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2018 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2037 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2057 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2068 GBV_ILN_2088 GBV_ILN_2093 GBV_ILN_2106 GBV_ILN_2108 GBV_ILN_2110 GBV_ILN_2111 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2119 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2144 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2188 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2472 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_2548 GBV_ILN_4012 GBV_ILN_4029 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4046 GBV_ILN_4112 GBV_ILN_4116 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4155 GBV_ILN_4242 GBV_ILN_4246 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4311 GBV_ILN_4313 GBV_ILN_4314 GBV_ILN_4318 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4328 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4336 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4598 GBV_ILN_4700 AR 36 2017 21 13 10 3250-3267 |
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Jia, Yonggen @@aut@@ Marq, Jean‐Baptiste @@aut@@ Bisio, Hugo @@aut@@ Jacot, Damien @@aut@@ Mueller, Christina @@aut@@ Yu, Lu @@aut@@ Choudhary, Jyoti @@aut@@ Brochet, Mathieu @@aut@@ Soldati‐Favre, Dominique @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000naa a22002652 4500</leader><controlfield tag="001">SPR058064478</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20241025065056.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">241025s2017 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.15252/embj.201796794</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR058064478</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)embj.201796794-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Jia, Yonggen</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2017</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="500" ind1=" " ind2=" "><subfield code="a">© The Authors 2017</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification.</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">acylation</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">cAMP‐dependent protein kinase A</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">cGMP‐dependent protein kinase G</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="650" ind1=" " ind2="4"><subfield code="a">egress</subfield><subfield code="7">(dpeaa)DE-He213</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Marq, Jean‐Baptiste</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bisio, Hugo</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Jacot, Damien</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Mueller, Christina</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yu, Lu</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Choudhary, Jyoti</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Brochet, Mathieu</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-3911-5537</subfield><subfield code="4">aut</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Soldati‐Favre, Dominique</subfield><subfield code="e">verfasserin</subfield><subfield code="0">(orcid)0000-0003-4156-2109</subfield><subfield code="4">aut</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="t">The EMBO Journal</subfield><subfield code="d">Nature Publishing Group UK, 2023</subfield><subfield code="g">36(2017), 21 vom: 13. 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Jia, Yonggen |
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Jia, Yonggen misc acylation misc cAMP‐dependent protein kinase A misc cGMP‐dependent protein kinase G misc egress Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii |
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Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii acylation (dpeaa)DE-He213 cAMP‐dependent protein kinase A (dpeaa)DE-He213 cGMP‐dependent protein kinase G (dpeaa)DE-He213 egress (dpeaa)DE-He213 |
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misc acylation misc cAMP‐dependent protein kinase A misc cGMP‐dependent protein kinase G misc egress |
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Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii |
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Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii |
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Jia, Yonggen |
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crosstalk between pka and pkg controls ph‐dependent host cell egress of toxoplasma gondii |
title_auth |
Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii |
abstract |
Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. © The Authors 2017 |
abstractGer |
Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. © The Authors 2017 |
abstract_unstemmed |
Abstract Toxoplasma gondii encodes three protein kinase A catalytic (PKAc1‐3) and one regulatory (PKAr) subunits to integrate cAMP‐dependent signals. Here, we show that inactive PKAc1 is maintained at the parasite pellicle by interacting with acylated PKAr. Either a conditional knockdown of PKAr or the overexpression of PKAc1 blocks parasite division. Conversely, down‐regulation of PKAc1 or stabilisation of a dominant‐negative PKAr isoform that does not bind cAMP triggers premature parasite egress from infected cells followed by serial invasion attempts leading to host cell lysis. This untimely egress depends on host cell acidification. A phosphoproteome analysis suggested the interplay between cAMP and cGMP signalling as PKAc1 inactivation changes the phosphorylation profile of a putative cGMP‐phosphodiesterase. Concordantly, inhibition of the cGMP‐dependent protein kinase G (PKG) blocks egress induced by PKAc1 inactivation or environmental acidification, while a cGMP‐phosphodiesterase inhibitor circumvents egress repression by PKAc1 or pH neutralisation. This indicates that pH and PKAc1 act as balancing regulators of cGMP metabolism to control egress. These results reveal a crosstalk between PKA and PKG pathways to govern egress in T. gondii. Synopsis In the human pathogen Toxoplasma gondii, the cAMP‐dependent protein kinase A1 (PKA1) prevents premature exit from the host cell induced by intracellular acidification. This is achieved by downregulating the activity of cGMP‐dependent protein kinase G (PKG). PKAc1 is maintained inactive at the pellicle by interacting with the dually acylated PKAr.Genetic perturbations of PKAc1 activity lead to premature egress of the parasite and unproductive invasion.PKG inhibitors block premature egress caused by PKAc1 inactivation.PKAc1 delays intracellular acidification–induced parasite exit from the host cell.PKAc1 and pH act as balancing regulators of PKG signalling to control parasite egress. Graphical Abstract PKA1 inhibits PKG activity to prevent premature parasite exit from the host cell due to intracellular acidification. © The Authors 2017 |
collection_details |
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title_short |
Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii |
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score |
7.400346 |