IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery

ABSTRACT In the human-pathogenic fungus Cryptococcus neoformans, the inositol polyphosphate signaling pathway is critical for virulence. We recently demonstrated the key role of the inositol pyrophosphate IP7 (isomer 5-PP-IP5) in driving fungal virulence; however, the mechanism of action remains elu...

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Autores principales:	Desmarini Desmarini, Sophie Lev, David Furkert, Ben Crossett, Adolfo Saiardi, Keren Kaufman-Francis, Cecilia Li, Tania C. Sorrell, Lorna Wilkinson-White, Jacqueline Matthews, Dorothea Fiedler, Julianne Teresa Djordjevic
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	IP7 inositol pyrophosphate inositol polyphosphate SPX domain cyclin-dependent kinase inhibitor PHO pathway Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/a8826e64d46d4f19bb5e464319b44f8e
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spelling	oai:doaj.org-article:a8826e64d46d4f19bb5e464319b44f8e2021-11-15T16:19:09ZIP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery10.1128/mBio.01920-202150-7511https://doaj.org/article/a8826e64d46d4f19bb5e464319b44f8e2020-10-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01920-20https://doaj.org/toc/2150-7511ABSTRACT In the human-pathogenic fungus Cryptococcus neoformans, the inositol polyphosphate signaling pathway is critical for virulence. We recently demonstrated the key role of the inositol pyrophosphate IP7 (isomer 5-PP-IP5) in driving fungal virulence; however, the mechanism of action remains elusive. Using genetic and biochemical approaches, and mouse infection models, we show that IP7 synthesized by Kcs1 regulates fungal virulence by binding to a conserved lysine surface cluster in the SPX domain of Pho81. Pho81 is the cyclin-dependent kinase (CDK) inhibitor of the phosphate signaling (PHO) pathway. We also provide novel mechanistic insight into the role of IP7 in PHO pathway regulation by demonstrating that IP7 functions as an intermolecular “glue” to stabilize Pho81 association with Pho85/Pho80 and, hence, promote PHO pathway activation and phosphate acquisition. Blocking IP7-Pho81 interaction using site-directed mutagenesis led to a dramatic loss of fungal virulence in a mouse infection model, and the effect was similar to that observed following PHO81 gene deletion, highlighting the key importance of Pho81 in fungal virulence. Furthermore, our findings provide additional evidence of evolutionary divergence in PHO pathway regulation in fungi by demonstrating that IP7 isomers have evolved different roles in PHO pathway control in C. neoformans and nonpathogenic yeast. IMPORTANCE Invasive fungal diseases pose a serious threat to human health globally with >1.5 million deaths occurring annually, 180,000 of which are attributable to the AIDS-related pathogen, Cryptococcus neoformans. Here, we demonstrate that interaction of the inositol pyrophosphate, IP7, with the CDK inhibitor protein, Pho81, is instrumental in promoting fungal virulence. IP7-Pho81 interaction stabilizes Pho81 association with other CDK complex components to promote PHO pathway activation and phosphate acquisition. Our data demonstrating that blocking IP7-Pho81 interaction or preventing Pho81 production leads to a dramatic loss in fungal virulence, coupled with Pho81 having no homologue in humans, highlights Pho81 function as a potential target for the development of urgently needed antifungal drugs.Desmarini DesmariniSophie LevDavid FurkertBen CrossettAdolfo SaiardiKeren Kaufman-FrancisCecilia LiTania C. SorrellLorna Wilkinson-WhiteJacqueline MatthewsDorothea FiedlerJulianne Teresa DjordjevicAmerican Society for MicrobiologyarticleIP7inositol pyrophosphateinositol polyphosphateSPX domaincyclin-dependent kinase inhibitorPHO pathwayMicrobiologyQR1-502ENmBio, Vol 11, Iss 5 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	IP7 inositol pyrophosphate inositol polyphosphate SPX domain cyclin-dependent kinase inhibitor PHO pathway Microbiology QR1-502
spellingShingle	IP7 inositol pyrophosphate inositol polyphosphate SPX domain cyclin-dependent kinase inhibitor PHO pathway Microbiology QR1-502 Desmarini Desmarini Sophie Lev David Furkert Ben Crossett Adolfo Saiardi Keren Kaufman-Francis Cecilia Li Tania C. Sorrell Lorna Wilkinson-White Jacqueline Matthews Dorothea Fiedler Julianne Teresa Djordjevic IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
description	ABSTRACT In the human-pathogenic fungus Cryptococcus neoformans, the inositol polyphosphate signaling pathway is critical for virulence. We recently demonstrated the key role of the inositol pyrophosphate IP7 (isomer 5-PP-IP5) in driving fungal virulence; however, the mechanism of action remains elusive. Using genetic and biochemical approaches, and mouse infection models, we show that IP7 synthesized by Kcs1 regulates fungal virulence by binding to a conserved lysine surface cluster in the SPX domain of Pho81. Pho81 is the cyclin-dependent kinase (CDK) inhibitor of the phosphate signaling (PHO) pathway. We also provide novel mechanistic insight into the role of IP7 in PHO pathway regulation by demonstrating that IP7 functions as an intermolecular “glue” to stabilize Pho81 association with Pho85/Pho80 and, hence, promote PHO pathway activation and phosphate acquisition. Blocking IP7-Pho81 interaction using site-directed mutagenesis led to a dramatic loss of fungal virulence in a mouse infection model, and the effect was similar to that observed following PHO81 gene deletion, highlighting the key importance of Pho81 in fungal virulence. Furthermore, our findings provide additional evidence of evolutionary divergence in PHO pathway regulation in fungi by demonstrating that IP7 isomers have evolved different roles in PHO pathway control in C. neoformans and nonpathogenic yeast. IMPORTANCE Invasive fungal diseases pose a serious threat to human health globally with >1.5 million deaths occurring annually, 180,000 of which are attributable to the AIDS-related pathogen, Cryptococcus neoformans. Here, we demonstrate that interaction of the inositol pyrophosphate, IP7, with the CDK inhibitor protein, Pho81, is instrumental in promoting fungal virulence. IP7-Pho81 interaction stabilizes Pho81 association with other CDK complex components to promote PHO pathway activation and phosphate acquisition. Our data demonstrating that blocking IP7-Pho81 interaction or preventing Pho81 production leads to a dramatic loss in fungal virulence, coupled with Pho81 having no homologue in humans, highlights Pho81 function as a potential target for the development of urgently needed antifungal drugs.
format	article
author	Desmarini Desmarini Sophie Lev David Furkert Ben Crossett Adolfo Saiardi Keren Kaufman-Francis Cecilia Li Tania C. Sorrell Lorna Wilkinson-White Jacqueline Matthews Dorothea Fiedler Julianne Teresa Djordjevic
author_facet	Desmarini Desmarini Sophie Lev David Furkert Ben Crossett Adolfo Saiardi Keren Kaufman-Francis Cecilia Li Tania C. Sorrell Lorna Wilkinson-White Jacqueline Matthews Dorothea Fiedler Julianne Teresa Djordjevic
author_sort	Desmarini Desmarini
title	IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
title_short	IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
title_full	IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
title_fullStr	IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
title_full_unstemmed	IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery
title_sort	ip<sub>7</sub>-spx domain interaction controls fungal virulence by stabilizing phosphate signaling machinery
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/a8826e64d46d4f19bb5e464319b44f8e
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IP<sub>7</sub>-SPX Domain Interaction Controls Fungal Virulence by Stabilizing Phosphate Signaling Machinery

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