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...
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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]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2017

Schlagwörter:	acylation cAMP‐dependent protein kinase A cGMP‐dependent protein kinase G egress

Anmerkung:	© The Authors 2017

Übergeordnetes Werk:	Enthalten in: The EMBO Journal - Nature Publishing Group UK, 2023, 36(2017), 21 vom: 13. Okt., Seite 3250-3267
Übergeordnetes Werk:	volume:36 ; year:2017 ; number:21 ; day:13 ; month:10 ; pages:3250-3267

Links:	Volltext

DOI / URN:	10.15252/embj.201796794

Katalog-ID:	SPR058064478

Internformat


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245	1	0	\|a Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
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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 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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912			\|a GBV_ILN_39
912			\|a GBV_ILN_40
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_72
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_90
912			\|a GBV_ILN_95
912			\|a GBV_ILN_100
912			\|a GBV_ILN_101
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_120
912			\|a GBV_ILN_138
912			\|a GBV_ILN_150
912			\|a GBV_ILN_151
912			\|a GBV_ILN_161
912			\|a GBV_ILN_168
912			\|a GBV_ILN_170
912			\|a GBV_ILN_171
912			\|a GBV_ILN_187
912			\|a GBV_ILN_211
912			\|a GBV_ILN_213
912			\|a GBV_ILN_224
912			\|a GBV_ILN_230
912			\|a GBV_ILN_252
912			\|a GBV_ILN_266
912			\|a GBV_ILN_285
912			\|a GBV_ILN_293
912			\|a GBV_ILN_602
912			\|a GBV_ILN_636
912			\|a GBV_ILN_702
912			\|a GBV_ILN_2001
912			\|a GBV_ILN_2003
912			\|a GBV_ILN_2004
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2006
912			\|a GBV_ILN_2007
912			\|a GBV_ILN_2008
912			\|a GBV_ILN_2009
912			\|a GBV_ILN_2010
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2015
912			\|a GBV_ILN_2018
912			\|a GBV_ILN_2020
912			\|a GBV_ILN_2021
912			\|a GBV_ILN_2025
912			\|a GBV_ILN_2026
912			\|a GBV_ILN_2027
912			\|a GBV_ILN_2034
912			\|a GBV_ILN_2037
912			\|a GBV_ILN_2038
912			\|a GBV_ILN_2044
912			\|a GBV_ILN_2048
912			\|a GBV_ILN_2049
912			\|a GBV_ILN_2050
912			\|a GBV_ILN_2055
912			\|a GBV_ILN_2056
912			\|a GBV_ILN_2057
912			\|a GBV_ILN_2059
912			\|a GBV_ILN_2061
912			\|a GBV_ILN_2064
912			\|a GBV_ILN_2068
912			\|a GBV_ILN_2088
912			\|a GBV_ILN_2093
912			\|a GBV_ILN_2106
912			\|a GBV_ILN_2108
912			\|a GBV_ILN_2110
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_2113
912			\|a GBV_ILN_2118
912			\|a GBV_ILN_2119
912			\|a GBV_ILN_2122
912			\|a GBV_ILN_2129
912			\|a GBV_ILN_2143
912			\|a GBV_ILN_2144
912			\|a GBV_ILN_2147
912			\|a GBV_ILN_2148
912			\|a GBV_ILN_2152
912			\|a GBV_ILN_2153
912			\|a GBV_ILN_2188
912			\|a GBV_ILN_2190
912			\|a GBV_ILN_2232
912			\|a GBV_ILN_2336
912			\|a GBV_ILN_2470
912			\|a GBV_ILN_2472
912			\|a GBV_ILN_2507
912			\|a GBV_ILN_2522
912			\|a GBV_ILN_2548
912			\|a GBV_ILN_4012
912			\|a GBV_ILN_4029
912			\|a GBV_ILN_4035
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4046
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4116
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4155
912			\|a GBV_ILN_4242
912			\|a GBV_ILN_4246
912			\|a GBV_ILN_4249
912			\|a GBV_ILN_4251
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4306
912			\|a GBV_ILN_4307
912			\|a GBV_ILN_4311
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4314
912			\|a GBV_ILN_4318
912			\|a GBV_ILN_4322
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4325
912			\|a GBV_ILN_4326
912			\|a GBV_ILN_4328
912			\|a GBV_ILN_4333
912			\|a GBV_ILN_4334
912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4336
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4367
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952			\|d 36 \|j 2017 \|e 21 \|b 13 \|c 10 \|h 3250-3267

Indexfelder

author_variant	y j yj j m jm h b hb d j dj c m cm l y ly j c jc m b mb d s ds
matchkey_str	article:14602075:2017----::rstlbtenkadkcnrlpdpnetotelge
hierarchy_sort_str	2017
publishDate	2017
allfields	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
allfields_unstemmed	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
allfieldsGer	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
allfieldsSound	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
language	English
source	Enthalten in The EMBO Journal 36(2017), 21 vom: 13. Okt., Seite 3250-3267 volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267
sourceStr	Enthalten in The EMBO Journal 36(2017), 21 vom: 13. Okt., Seite 3250-3267 volume:36 year:2017 number:21 day:13 month:10 pages:3250-3267
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	acylation cAMP‐dependent protein kinase A cGMP‐dependent protein kinase G egress
isfreeaccess_bool	false
container_title	The EMBO Journal
authorswithroles_txt_mv	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@@
publishDateDaySort_date	2017-10-13T00:00:00Z
hierarchy_top_id	266022529
id	SPR058064478
language_de	englisch
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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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author	Jia, Yonggen
spellingShingle	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
authorStr	Jia, Yonggen
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topic_title	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
topic	misc acylation misc cAMP‐dependent protein kinase A misc cGMP‐dependent protein kinase G misc egress
topic_unstemmed	misc acylation misc cAMP‐dependent protein kinase A misc cGMP‐dependent protein kinase G misc egress
topic_browse	misc acylation misc cAMP‐dependent protein kinase A misc cGMP‐dependent protein kinase G misc egress
format_facet	Elektronische Aufsätze Aufsätze Elektronische Ressource
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title	Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
ctrlnum	(DE-627)SPR058064478 (SPR)embj.201796794-e
title_full	Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
author_sort	Jia, Yonggen
journal	The EMBO Journal
journalStr	The EMBO Journal
lang_code	eng
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container_start_page	3250
author_browse	Jia, Yonggen Marq, Jean‐Baptiste Bisio, Hugo Jacot, Damien Mueller, Christina Yu, Lu Choudhary, Jyoti Brochet, Mathieu Soldati‐Favre, Dominique
container_volume	36
format_se	Elektronische Aufsätze
author-letter	Jia, Yonggen
doi_str_mv	10.15252/embj.201796794
normlink	(ORCID)0000-0003-3911-5537 (ORCID)0000-0003-4156-2109
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title_sort	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
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container_issue	21
title_short	Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii
url	https://dx.doi.org/10.15252/embj.201796794
remote_bool	true
author2	Marq, Jean‐Baptiste Bisio, Hugo Jacot, Damien Mueller, Christina Yu, Lu Choudhary, Jyoti Brochet, Mathieu Soldati‐Favre, Dominique
author2Str	Marq, Jean‐Baptiste Bisio, Hugo Jacot, Damien Mueller, Christina Yu, Lu Choudhary, Jyoti Brochet, Mathieu Soldati‐Favre, Dominique
ppnlink	266022529
mediatype_str_mv	c
isOA_txt	false
hochschulschrift_bool	false
doi_str	10.15252/embj.201796794
up_date	2024-10-25T04:56:03.792Z
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Crosstalk between PKA and PKG controls pH‐dependent host cell egress of Toxoplasma gondii

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