Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex

ABSTRACT Species of the Legionella genus encode at least 18,000 effector proteins that are translocated through the Dot/Icm type IVB translocation system into macrophages and protist hosts to enable intracellular growth. Eight effectors, including ankyrin H (AnkH), are common to all Legionella speci...

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Autores principales:	Juanita Von Dwingelo, Ivy Yeuk Wah Chung, Christopher T. Price, Lei Li, Snake Jones, Miroslaw Cygler, Yousef Abu Kwaik
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2019
Materias:	AnkH Dot/Icm type IVB secretion system LARP7 Legionella pneumophila effector functions transcriptional regulation Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7bfe82e9c20c4ed9a96d335fee24c1d8
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spelling	oai:doaj.org-article:7bfe82e9c20c4ed9a96d335fee24c1d82021-11-15T16:22:11ZInteraction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex10.1128/mBio.01942-192150-7511https://doaj.org/article/7bfe82e9c20c4ed9a96d335fee24c1d82019-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01942-19https://doaj.org/toc/2150-7511ABSTRACT Species of the Legionella genus encode at least 18,000 effector proteins that are translocated through the Dot/Icm type IVB translocation system into macrophages and protist hosts to enable intracellular growth. Eight effectors, including ankyrin H (AnkH), are common to all Legionella species. The AnkH effector is also present in Coxiella and Rickettsiella. To date, no pathogenic effectors have ever been described that directly interfere with host cell transcription. We determined that the host nuclear protein La-related protein 7 (LARP7), which is a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, interacts with AnkH in the host cell nucleus. The AnkH-LARP7 interaction partially impedes interactions of the 7SK snRNP components with LARP7, interfering with transcriptional elongation by polymerase (Pol) II. Consistent with that, our data show AnkH-dependent global reprogramming of transcription of macrophages infected by Legionella pneumophila. The crystal structure of AnkH shows that it contains four N-terminal ankyrin repeats, followed by a cysteine protease-like domain and an α-helical C-terminal domain. A substitution within the β-hairpin loop of the third ankyrin repeat results in diminishment of LARP7-AnkH interactions and phenocopies the ankH null mutant defect in intracellular growth. LARP7 knockdown partially suppresses intracellular proliferation of wild-type (WT) bacteria and increases the severity of the defect of the ΔankH mutant, indicating a role for LARP7 in permissiveness of host cells to intracellular bacterial infection. We conclude that the AnkH-LARP7 interaction impedes interaction of LARP7 with 7SK snRNP, which would block transcriptional elongation by Pol II, leading to host global transcriptional reprogramming and permissiveness to L. pneumophila. IMPORTANCE For intracellular pathogens to thrive in host cells, an environment that supports survival and replication needs to be established. L. pneumophila accomplishes this through the activity of the ∼330 effector proteins that are injected into host cells during infection. Effector functions range from hijacking host trafficking pathways to altering host cell machinery, resulting in altered cell biology and innate immunity. One such pathway is the host protein synthesis pathway. Five L. pneumophila effectors have been identified that alter host cell translation, and 2 effectors have been identified that indirectly affect host cell transcription. No pathogenic effectors have been described that directly interfere with host cell transcription. Here we show a direct interaction of the AnkH effector with a host cell transcription complex involved in transcriptional elongation. We identify a novel process by which AnkH interferes with host transcriptional elongation through interference with formation of a functional complex and show that this interference is required for pathogen proliferation.Juanita Von DwingeloIvy Yeuk Wah ChungChristopher T. PriceLei LiSnake JonesMiroslaw CyglerYousef Abu KwaikAmerican Society for MicrobiologyarticleAnkHDot/Icm type IVB secretion systemLARP7Legionella pneumophilaeffector functionstranscriptional regulationMicrobiologyQR1-502ENmBio, Vol 10, Iss 4 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	AnkH Dot/Icm type IVB secretion system LARP7 Legionella pneumophila effector functions transcriptional regulation Microbiology QR1-502
spellingShingle	AnkH Dot/Icm type IVB secretion system LARP7 Legionella pneumophila effector functions transcriptional regulation Microbiology QR1-502 Juanita Von Dwingelo Ivy Yeuk Wah Chung Christopher T. Price Lei Li Snake Jones Miroslaw Cygler Yousef Abu Kwaik Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex
description	ABSTRACT Species of the Legionella genus encode at least 18,000 effector proteins that are translocated through the Dot/Icm type IVB translocation system into macrophages and protist hosts to enable intracellular growth. Eight effectors, including ankyrin H (AnkH), are common to all Legionella species. The AnkH effector is also present in Coxiella and Rickettsiella. To date, no pathogenic effectors have ever been described that directly interfere with host cell transcription. We determined that the host nuclear protein La-related protein 7 (LARP7), which is a component of the 7SK small nuclear ribonucleoprotein (snRNP) complex, interacts with AnkH in the host cell nucleus. The AnkH-LARP7 interaction partially impedes interactions of the 7SK snRNP components with LARP7, interfering with transcriptional elongation by polymerase (Pol) II. Consistent with that, our data show AnkH-dependent global reprogramming of transcription of macrophages infected by Legionella pneumophila. The crystal structure of AnkH shows that it contains four N-terminal ankyrin repeats, followed by a cysteine protease-like domain and an α-helical C-terminal domain. A substitution within the β-hairpin loop of the third ankyrin repeat results in diminishment of LARP7-AnkH interactions and phenocopies the ankH null mutant defect in intracellular growth. LARP7 knockdown partially suppresses intracellular proliferation of wild-type (WT) bacteria and increases the severity of the defect of the ΔankH mutant, indicating a role for LARP7 in permissiveness of host cells to intracellular bacterial infection. We conclude that the AnkH-LARP7 interaction impedes interaction of LARP7 with 7SK snRNP, which would block transcriptional elongation by Pol II, leading to host global transcriptional reprogramming and permissiveness to L. pneumophila. IMPORTANCE For intracellular pathogens to thrive in host cells, an environment that supports survival and replication needs to be established. L. pneumophila accomplishes this through the activity of the ∼330 effector proteins that are injected into host cells during infection. Effector functions range from hijacking host trafficking pathways to altering host cell machinery, resulting in altered cell biology and innate immunity. One such pathway is the host protein synthesis pathway. Five L. pneumophila effectors have been identified that alter host cell translation, and 2 effectors have been identified that indirectly affect host cell transcription. No pathogenic effectors have been described that directly interfere with host cell transcription. Here we show a direct interaction of the AnkH effector with a host cell transcription complex involved in transcriptional elongation. We identify a novel process by which AnkH interferes with host transcriptional elongation through interference with formation of a functional complex and show that this interference is required for pathogen proliferation.
format	article
author	Juanita Von Dwingelo Ivy Yeuk Wah Chung Christopher T. Price Lei Li Snake Jones Miroslaw Cygler Yousef Abu Kwaik
author_facet	Juanita Von Dwingelo Ivy Yeuk Wah Chung Christopher T. Price Lei Li Snake Jones Miroslaw Cygler Yousef Abu Kwaik
author_sort	Juanita Von Dwingelo
title	Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex
title_short	Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex
title_full	Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex
title_fullStr	Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex
title_full_unstemmed	Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex
title_sort	interaction of the ankyrin h core effector of <italic toggle="yes">legionella</italic> with the host larp7 component of the 7sk snrnp complex
publisher	American Society for Microbiology
publishDate	2019
url	https://doaj.org/article/7bfe82e9c20c4ed9a96d335fee24c1d8
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Interaction of the Ankyrin H Core Effector of <italic toggle="yes">Legionella</italic> with the Host LARP7 Component of the 7SK snRNP Complex

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