Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle

ABSTRACT Intracellular bacterial pathogens remodel cellular functions during their infectious cycle via the coordinated actions of effector molecules delivered through dedicated secretion systems. While the function of many individual effectors is known, how they interact to promote pathogenesis is...

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Autores principales:	Erin P. Smith, Alexis Cotto-Rosario, Elizabeth Borghesan, Kiara Held, Cheryl N. Miller, Jean Celli
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	Brucella Rab2 type IV secretion epistasis macrophage pathogenesis Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/f7dfe2eccd2248279ea9482b3b7e79ea
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spelling	oai:doaj.org-article:f7dfe2eccd2248279ea9482b3b7e79ea2021-11-15T15:57:03ZEpistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle10.1128/mBio.03350-192150-7511https://doaj.org/article/f7dfe2eccd2248279ea9482b3b7e79ea2020-04-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03350-19https://doaj.org/toc/2150-7511ABSTRACT Intracellular bacterial pathogens remodel cellular functions during their infectious cycle via the coordinated actions of effector molecules delivered through dedicated secretion systems. While the function of many individual effectors is known, how they interact to promote pathogenesis is rarely understood. The zoonotic bacterium Brucella abortus, the causative agent of brucellosis, delivers effector proteins via its VirB type IV secretion system (T4SS) which mediate biogenesis of the endoplasmic reticulum (ER)-derived replicative Brucella-containing vacuole (rBCV). Here, we show that T4SS effectors BspB and RicA display epistatic interactions in Brucella replication. Defects in rBCV biogenesis and Brucella replication caused by deletion of bspB were dependent on the host GTPase Rab2a and suppressed by the deletion of ricA, indicating a role of Rab2-binding effector RicA in these phenotypic defects. Rab2a requirements for rBCV biogenesis and Brucella intracellular replication were abolished upon deletion of both bspB and ricA, demonstrating that the functional interaction of these effectors engages Rab2-dependent transport in the Brucella intracellular cycle. Expression of RicA impaired host secretion and caused Golgi fragmentation. While BspB-mediated changes in ER-to-Golgi transport were independent of RicA and Rab2a, BspB-driven alterations in Golgi vesicular traffic also involved RicA and Rab2a, defining BspB and RicA’s functional interplay at the Golgi interface. Altogether, these findings support a model where RicA modulation of Rab2a functions impairs Brucella replication but is compensated by BspB-mediated remodeling of Golgi apparatus-associated vesicular transport, revealing an epistatic interaction between these T4SS effectors. IMPORTANCE Bacterial pathogens with an intracellular lifestyle modulate many host cellular processes to promote their infectious cycle. They do so by delivering effector proteins into host cells via dedicated secretion systems that target specific host functions. While the roles of many individual effectors are known, how their modes of action are coordinated is rarely understood. Here, we show that the zoonotic bacterium Brucella abortus delivers the BspB effector that mitigates the negative effect on bacterial replication that the RicA effector exerts via modulation of the host small GTPase Rab2. These findings provide an example of functional integration between bacterial effectors that promotes proliferation of pathogens.Erin P. SmithAlexis Cotto-RosarioElizabeth BorghesanKiara HeldCheryl N. MillerJean CelliAmerican Society for MicrobiologyarticleBrucellaRab2type IV secretionepistasismacrophagepathogenesisMicrobiologyQR1-502ENmBio, Vol 11, Iss 2 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Brucella Rab2 type IV secretion epistasis macrophage pathogenesis Microbiology QR1-502
spellingShingle	Brucella Rab2 type IV secretion epistasis macrophage pathogenesis Microbiology QR1-502 Erin P. Smith Alexis Cotto-Rosario Elizabeth Borghesan Kiara Held Cheryl N. Miller Jean Celli Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle
description	ABSTRACT Intracellular bacterial pathogens remodel cellular functions during their infectious cycle via the coordinated actions of effector molecules delivered through dedicated secretion systems. While the function of many individual effectors is known, how they interact to promote pathogenesis is rarely understood. The zoonotic bacterium Brucella abortus, the causative agent of brucellosis, delivers effector proteins via its VirB type IV secretion system (T4SS) which mediate biogenesis of the endoplasmic reticulum (ER)-derived replicative Brucella-containing vacuole (rBCV). Here, we show that T4SS effectors BspB and RicA display epistatic interactions in Brucella replication. Defects in rBCV biogenesis and Brucella replication caused by deletion of bspB were dependent on the host GTPase Rab2a and suppressed by the deletion of ricA, indicating a role of Rab2-binding effector RicA in these phenotypic defects. Rab2a requirements for rBCV biogenesis and Brucella intracellular replication were abolished upon deletion of both bspB and ricA, demonstrating that the functional interaction of these effectors engages Rab2-dependent transport in the Brucella intracellular cycle. Expression of RicA impaired host secretion and caused Golgi fragmentation. While BspB-mediated changes in ER-to-Golgi transport were independent of RicA and Rab2a, BspB-driven alterations in Golgi vesicular traffic also involved RicA and Rab2a, defining BspB and RicA’s functional interplay at the Golgi interface. Altogether, these findings support a model where RicA modulation of Rab2a functions impairs Brucella replication but is compensated by BspB-mediated remodeling of Golgi apparatus-associated vesicular transport, revealing an epistatic interaction between these T4SS effectors. IMPORTANCE Bacterial pathogens with an intracellular lifestyle modulate many host cellular processes to promote their infectious cycle. They do so by delivering effector proteins into host cells via dedicated secretion systems that target specific host functions. While the roles of many individual effectors are known, how their modes of action are coordinated is rarely understood. Here, we show that the zoonotic bacterium Brucella abortus delivers the BspB effector that mitigates the negative effect on bacterial replication that the RicA effector exerts via modulation of the host small GTPase Rab2. These findings provide an example of functional integration between bacterial effectors that promotes proliferation of pathogens.
format	article
author	Erin P. Smith Alexis Cotto-Rosario Elizabeth Borghesan Kiara Held Cheryl N. Miller Jean Celli
author_facet	Erin P. Smith Alexis Cotto-Rosario Elizabeth Borghesan Kiara Held Cheryl N. Miller Jean Celli
author_sort	Erin P. Smith
title	Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle
title_short	Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle
title_full	Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle
title_fullStr	Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle
title_full_unstemmed	Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle
title_sort	epistatic interplay between type iv secretion effectors engages the small gtpase rab2 in the <italic toggle="yes">brucella</italic> intracellular cycle
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/f7dfe2eccd2248279ea9482b3b7e79ea
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Epistatic Interplay between Type IV Secretion Effectors Engages the Small GTPase Rab2 in the <italic toggle="yes">Brucella</italic> Intracellular Cycle

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