Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD

ABSTRACT Type III secretion systems (T3SS) translocate effector proteins into target cells in order to disrupt or modulate host cell signaling pathways and establish replicative niches. However, recognition of T3SS activity by cytosolic pattern recognition receptors (PRRs) of the nucleotide-binding...

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Autores principales:	Erin E. Zwack, Annelise G. Snyder, Meghan A. Wynosky-Dolfi, Gordon Ruthel, Naomi H. Philip, Melanie M. Marketon, Matthew S. Francis, James B. Bliska, Igor E. Brodsky
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Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7f64c014a5aa4c928925802ef24e358f
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spelling	oai:doaj.org-article:7f64c014a5aa4c928925802ef24e358f2021-11-15T15:41:18ZInflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD10.1128/mBio.02095-142150-7511https://doaj.org/article/7f64c014a5aa4c928925802ef24e358f2015-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02095-14https://doaj.org/toc/2150-7511ABSTRACT Type III secretion systems (T3SS) translocate effector proteins into target cells in order to disrupt or modulate host cell signaling pathways and establish replicative niches. However, recognition of T3SS activity by cytosolic pattern recognition receptors (PRRs) of the nucleotide-binding domain leucine rich repeat (NLR) family, either through detection of translocated products or membrane disruption, induces assembly of multiprotein complexes known as inflammasomes. Macrophages infected with Yersinia pseudotuberculosis strains lacking all known effectors or lacking the translocation regulator YopK induce rapid activation of both the canonical NLRP3 and noncanonical caspase-11 inflammasomes. While this inflammasome activation requires a functional T3SS, the precise signal that triggers inflammasome activation in response to Yersinia T3SS activity remains unclear. Effectorless strains of Yersinia as well as ΔyopK strains translocate elevated levels of T3SS substrates into infected cells. To dissect the contribution of pore formation and translocation to inflammasome activation, we took advantage of variants of YopD and LcrH that separate these functions of the T3SS. Notably, YopD variants that abrogated translocation but not pore-forming activity failed to induce inflammasome activation. Furthermore, analysis of individual infected cells revealed that inflammasome activation at the single-cell level correlated with translocated levels of YopB and YopD themselves. Intriguingly, LcrH mutants that are fully competent for effector translocation but produce and translocate lower levels of YopB and YopD also fail to trigger inflammasome activation. Our findings therefore suggest that hypertranslocation of YopD and YopB is linked to inflammasome activation in response to the Yersinia T3SS. IMPORTANCE The innate immune response is critical to effective clearance of pathogens. Recognition of conserved virulence structures and activities by innate immune receptors such as NLRs constitute one of the first steps in mounting the innate immune response. However, pathogens such as Yersinia actively evade or subvert components of host defense, such as inflammasomes. The T3SS-secreted protein YopK is an essential virulence factor that limits translocation of other Yops, thereby limiting T3SS-induced inflammasome activation. However, what triggers inflammasome activation in cells infected by YopK-deficient Yersinia is not clear. Our findings indicate that hypertranslocation of pore complex proteins promotes inflammasome activation and that YopK prevents inflammasome activation by the T3SS by limiting translocation of YopD and YopB themselves.Erin E. ZwackAnnelise G. SnyderMeghan A. Wynosky-DolfiGordon RuthelNaomi H. PhilipMelanie M. MarketonMatthew S. FrancisJames B. BliskaIgor E. BrodskyAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 1 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Erin E. Zwack Annelise G. Snyder Meghan A. Wynosky-Dolfi Gordon Ruthel Naomi H. Philip Melanie M. Marketon Matthew S. Francis James B. Bliska Igor E. Brodsky Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD
description	ABSTRACT Type III secretion systems (T3SS) translocate effector proteins into target cells in order to disrupt or modulate host cell signaling pathways and establish replicative niches. However, recognition of T3SS activity by cytosolic pattern recognition receptors (PRRs) of the nucleotide-binding domain leucine rich repeat (NLR) family, either through detection of translocated products or membrane disruption, induces assembly of multiprotein complexes known as inflammasomes. Macrophages infected with Yersinia pseudotuberculosis strains lacking all known effectors or lacking the translocation regulator YopK induce rapid activation of both the canonical NLRP3 and noncanonical caspase-11 inflammasomes. While this inflammasome activation requires a functional T3SS, the precise signal that triggers inflammasome activation in response to Yersinia T3SS activity remains unclear. Effectorless strains of Yersinia as well as ΔyopK strains translocate elevated levels of T3SS substrates into infected cells. To dissect the contribution of pore formation and translocation to inflammasome activation, we took advantage of variants of YopD and LcrH that separate these functions of the T3SS. Notably, YopD variants that abrogated translocation but not pore-forming activity failed to induce inflammasome activation. Furthermore, analysis of individual infected cells revealed that inflammasome activation at the single-cell level correlated with translocated levels of YopB and YopD themselves. Intriguingly, LcrH mutants that are fully competent for effector translocation but produce and translocate lower levels of YopB and YopD also fail to trigger inflammasome activation. Our findings therefore suggest that hypertranslocation of YopD and YopB is linked to inflammasome activation in response to the Yersinia T3SS. IMPORTANCE The innate immune response is critical to effective clearance of pathogens. Recognition of conserved virulence structures and activities by innate immune receptors such as NLRs constitute one of the first steps in mounting the innate immune response. However, pathogens such as Yersinia actively evade or subvert components of host defense, such as inflammasomes. The T3SS-secreted protein YopK is an essential virulence factor that limits translocation of other Yops, thereby limiting T3SS-induced inflammasome activation. However, what triggers inflammasome activation in cells infected by YopK-deficient Yersinia is not clear. Our findings indicate that hypertranslocation of pore complex proteins promotes inflammasome activation and that YopK prevents inflammasome activation by the T3SS by limiting translocation of YopD and YopB themselves.
format	article
author	Erin E. Zwack Annelise G. Snyder Meghan A. Wynosky-Dolfi Gordon Ruthel Naomi H. Philip Melanie M. Marketon Matthew S. Francis James B. Bliska Igor E. Brodsky
author_facet	Erin E. Zwack Annelise G. Snyder Meghan A. Wynosky-Dolfi Gordon Ruthel Naomi H. Philip Melanie M. Marketon Matthew S. Francis James B. Bliska Igor E. Brodsky
author_sort	Erin E. Zwack
title	Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD
title_short	Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD
title_full	Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD
title_fullStr	Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD
title_full_unstemmed	Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD
title_sort	inflammasome activation in response to the yersinia type iii secretion system requires hyperinjection of translocon proteins yopb and yopd
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/7f64c014a5aa4c928925802ef24e358f
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Inflammasome Activation in Response to the Yersinia Type III Secretion System Requires Hyperinjection of Translocon Proteins YopB and YopD

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