Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival

ABSTRACT To establish a habitable intracellular niche, various pathogenic bacteria secrete effectors that target intracellular trafficking and modulate phosphoinositide (PI) metabolism. Murine typhus, caused by the obligate intracellular bacterium Rickettsia typhi, remains a severe disease in humans...

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Autores principales:	Oliver H. Voss, Joseph J. Gillespie, Stephanie S. Lehman, Sherri A. Rennoll, Magda Beier-Sexton, M. Sayeedur Rahman, Abdu F. Azad
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	R. typhi Risk1 Rab5 EEA1 ubiquitin Beclin-1 Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/b7604d98ff0c4fd89718fd07704ce847
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spelling	oai:doaj.org-article:b7604d98ff0c4fd89718fd07704ce8472021-11-15T15:56:47ZRisk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival10.1128/mBio.00820-202150-7511https://doaj.org/article/b7604d98ff0c4fd89718fd07704ce8472020-06-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00820-20https://doaj.org/toc/2150-7511ABSTRACT To establish a habitable intracellular niche, various pathogenic bacteria secrete effectors that target intracellular trafficking and modulate phosphoinositide (PI) metabolism. Murine typhus, caused by the obligate intracellular bacterium Rickettsia typhi, remains a severe disease in humans. However, the mechanisms by which R. typhi effector molecules contribute to internalization by induced phagocytosis and subsequent phagosomal escape into the cytosol to facilitate the intracellular growth of the bacteria remain ill-defined. Here, we characterize a new molecule, Risk1, as a phosphatidylinositol 3-kinase (PI3K) secreted effector and the first bacterial secretory kinase with both class I and III PI3K activities. Inactivation of Risk1 PI3K activities reduced the phosphorylation of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate within the host, which consequently diminished host colonization by R. typhi. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. Subsequently, R. typhi undergoes ubiquitination and induces host autophagy; however, maturation to autolysosomes is subverted to support intracellular growth. Intriguingly, only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to R. typhi-induced autophagosome formation. In sum, our data suggest that Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of R. typhi. IMPORTANCE Rickettsia species are Gram-negative obligate intracellular bacteria that infect a wide range of eukaryotes and vertebrates. In particular, human body louse-borne Rickettsia prowazekii and flea-borne Rickettsia typhi have historically plagued humankind and continue to reemerge globally. The unavailability of vaccines and limited effectiveness of antibiotics late in infection place lethality rates up to 30%, highlighting the need to elucidate the mechanisms of Rickettsia pathogenicity in greater detail. Here, we characterize a new effector, Risk1, as a secreted phosphatidylinositol 3-kinase (PI3K) with unique dual class I and class III activities. Risk1 is required for host colonization, and its vacuolar phosphatidylinositol 3-phosphate generation modulates endosomal trafficking to arrest autophagosomal maturation. Collectively, Risk1 facilitates R. typhi growth by altering phosphoinositide metabolism and subverting intracellular trafficking.Oliver H. VossJoseph J. GillespieStephanie S. LehmanSherri A. RennollMagda Beier-SextonM. Sayeedur RahmanAbdu F. AzadAmerican Society for MicrobiologyarticleR. typhiRisk1Rab5EEA1ubiquitinBeclin-1MicrobiologyQR1-502ENmBio, Vol 11, Iss 3 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	R. typhi Risk1 Rab5 EEA1 ubiquitin Beclin-1 Microbiology QR1-502
spellingShingle	R. typhi Risk1 Rab5 EEA1 ubiquitin Beclin-1 Microbiology QR1-502 Oliver H. Voss Joseph J. Gillespie Stephanie S. Lehman Sherri A. Rennoll Magda Beier-Sexton M. Sayeedur Rahman Abdu F. Azad Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival
description	ABSTRACT To establish a habitable intracellular niche, various pathogenic bacteria secrete effectors that target intracellular trafficking and modulate phosphoinositide (PI) metabolism. Murine typhus, caused by the obligate intracellular bacterium Rickettsia typhi, remains a severe disease in humans. However, the mechanisms by which R. typhi effector molecules contribute to internalization by induced phagocytosis and subsequent phagosomal escape into the cytosol to facilitate the intracellular growth of the bacteria remain ill-defined. Here, we characterize a new molecule, Risk1, as a phosphatidylinositol 3-kinase (PI3K) secreted effector and the first bacterial secretory kinase with both class I and III PI3K activities. Inactivation of Risk1 PI3K activities reduced the phosphorylation of phosphatidylinositol 4,5-bisphosphate to phosphatidylinositol 3,4,5-trisphosphate within the host, which consequently diminished host colonization by R. typhi. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. Subsequently, R. typhi undergoes ubiquitination and induces host autophagy; however, maturation to autolysosomes is subverted to support intracellular growth. Intriguingly, only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to R. typhi-induced autophagosome formation. In sum, our data suggest that Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of R. typhi. IMPORTANCE Rickettsia species are Gram-negative obligate intracellular bacteria that infect a wide range of eukaryotes and vertebrates. In particular, human body louse-borne Rickettsia prowazekii and flea-borne Rickettsia typhi have historically plagued humankind and continue to reemerge globally. The unavailability of vaccines and limited effectiveness of antibiotics late in infection place lethality rates up to 30%, highlighting the need to elucidate the mechanisms of Rickettsia pathogenicity in greater detail. Here, we characterize a new effector, Risk1, as a secreted phosphatidylinositol 3-kinase (PI3K) with unique dual class I and class III activities. Risk1 is required for host colonization, and its vacuolar phosphatidylinositol 3-phosphate generation modulates endosomal trafficking to arrest autophagosomal maturation. Collectively, Risk1 facilitates R. typhi growth by altering phosphoinositide metabolism and subverting intracellular trafficking.
format	article
author	Oliver H. Voss Joseph J. Gillespie Stephanie S. Lehman Sherri A. Rennoll Magda Beier-Sexton M. Sayeedur Rahman Abdu F. Azad
author_facet	Oliver H. Voss Joseph J. Gillespie Stephanie S. Lehman Sherri A. Rennoll Magda Beier-Sexton M. Sayeedur Rahman Abdu F. Azad
author_sort	Oliver H. Voss
title	Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival
title_short	Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival
title_full	Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival
title_fullStr	Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival
title_full_unstemmed	Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival
title_sort	risk1, a phosphatidylinositol 3-kinase effector, promotes <named-content content-type="genus-species">rickettsia typhi</named-content> intracellular survival
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/b7604d98ff0c4fd89718fd07704ce847
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Risk1, a Phosphatidylinositol 3-Kinase Effector, Promotes <named-content content-type="genus-species">Rickettsia typhi</named-content> Intracellular Survival

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