Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System

ABSTRACT Bacterial lipoproteins (Lpps) are a class of membrane-associated proteins universally distributed among all bacteria. A characteristic N-terminal cysteine residue that is variably acylated anchors C-terminal globular domains to the extracellular surface, where they serve numerous roles, inc...

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Autores principales: John H. Gardiner, Gloria Komazin, Miki Matsuo, Kaitlin Cole, Friedrich Götz, Timothy C. Meredith
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Publicado: American Society for Microbiology 2020
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spelling oai:doaj.org-article:0dc2e21b11354398ab1fff8f781581462021-11-15T15:56:43ZLipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System10.1128/mBio.01619-202150-7511https://doaj.org/article/0dc2e21b11354398ab1fff8f781581462020-08-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01619-20https://doaj.org/toc/2150-7511ABSTRACT Bacterial lipoproteins (Lpps) are a class of membrane-associated proteins universally distributed among all bacteria. A characteristic N-terminal cysteine residue that is variably acylated anchors C-terminal globular domains to the extracellular surface, where they serve numerous roles, including in the capture and transport of essential nutrients. Lpps are also ligands for the Toll-like receptor 2 (TLR2) family, a key component of the innate immune system tasked with bacterial recognition. While Lpp function is conserved in all prokaryotes, structural heterogeneity in the N-terminal acylation state is widespread among Firmicutes and can differ between otherwise closely related species. In this study, we identify a novel two-gene system that directs the synthesis of N-acylated Lpps in the commensal and opportunistic pathogen subset of staphylococci. The two genes, which we have named the lipoprotein N-acylation transferase system (Lns), bear no resemblance to previously characterized N-terminal Lpp tailoring enzymes. LnsA (SAOUHSC_00822) is an NlpC/P60 superfamily enzyme, whereas LnsB (SAOHSC_02761) has remote homology to the CAAX protease and bacteriocin-processing enzyme (CPBP) family. Both LnsA and LnsB are together necessary and alone sufficient for N-acylation in Staphylococcus aureus and convert the Lpp chemotype from diacyl to triacyl when heterologously expressed in Listeria monocytogenes. Acquisition of lnsAB decreases TLR2-mediated detection of S. aureus by nearly 10-fold and shifts the activated TLR2 complex from TLR2/6 to TLR2/1. LnsAB thus has a dual role in attenuating TLR2 signaling in addition to a broader role in bacterial cell envelope physiology. IMPORTANCE Although it has long been known that S. aureus forms triacylated Lpps, a lack of homologs to known N-acylation genes found in Gram-negative bacteria has until now precluded identification of the genes responsible for this Lpp modification. Here, we demonstrate N-terminal Lpp acylation and chemotype conversion to the tri-acylated state is directed by a unique acyl transferase system encoded by two noncontiguous staphylococci genes (lnsAB). Since triacylated Lpps stimulate TLR2 more weakly than their diacylated counterparts, Lpp N-acylation is an important TLR2 immunoevasion factor for determining tolerance or nontolerance in niches such as in the skin microbiota. The discovery of the LnsAB system expands the known diversity of Lpp biosynthesis pathways and acyl transfer biochemistry in bacteria, advances our understanding of Lpp structural heterogeneity, and helps differentiate commensal and noncommensal microbiota.John H. GardinerGloria KomazinMiki MatsuoKaitlin ColeFriedrich GötzTimothy C. MeredithAmerican Society for MicrobiologyarticleStaphylococcusStaphylococcus aureusTLR2acyl transferasesimmune responselipoproteinsMicrobiologyQR1-502ENmBio, Vol 11, Iss 4 (2020)
institution DOAJ
collection DOAJ
language EN
topic Staphylococcus
Staphylococcus aureus
TLR2
acyl transferases
immune response
lipoproteins
Microbiology
QR1-502
spellingShingle Staphylococcus
Staphylococcus aureus
TLR2
acyl transferases
immune response
lipoproteins
Microbiology
QR1-502
John H. Gardiner
Gloria Komazin
Miki Matsuo
Kaitlin Cole
Friedrich Götz
Timothy C. Meredith
Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System
description ABSTRACT Bacterial lipoproteins (Lpps) are a class of membrane-associated proteins universally distributed among all bacteria. A characteristic N-terminal cysteine residue that is variably acylated anchors C-terminal globular domains to the extracellular surface, where they serve numerous roles, including in the capture and transport of essential nutrients. Lpps are also ligands for the Toll-like receptor 2 (TLR2) family, a key component of the innate immune system tasked with bacterial recognition. While Lpp function is conserved in all prokaryotes, structural heterogeneity in the N-terminal acylation state is widespread among Firmicutes and can differ between otherwise closely related species. In this study, we identify a novel two-gene system that directs the synthesis of N-acylated Lpps in the commensal and opportunistic pathogen subset of staphylococci. The two genes, which we have named the lipoprotein N-acylation transferase system (Lns), bear no resemblance to previously characterized N-terminal Lpp tailoring enzymes. LnsA (SAOUHSC_00822) is an NlpC/P60 superfamily enzyme, whereas LnsB (SAOHSC_02761) has remote homology to the CAAX protease and bacteriocin-processing enzyme (CPBP) family. Both LnsA and LnsB are together necessary and alone sufficient for N-acylation in Staphylococcus aureus and convert the Lpp chemotype from diacyl to triacyl when heterologously expressed in Listeria monocytogenes. Acquisition of lnsAB decreases TLR2-mediated detection of S. aureus by nearly 10-fold and shifts the activated TLR2 complex from TLR2/6 to TLR2/1. LnsAB thus has a dual role in attenuating TLR2 signaling in addition to a broader role in bacterial cell envelope physiology. IMPORTANCE Although it has long been known that S. aureus forms triacylated Lpps, a lack of homologs to known N-acylation genes found in Gram-negative bacteria has until now precluded identification of the genes responsible for this Lpp modification. Here, we demonstrate N-terminal Lpp acylation and chemotype conversion to the tri-acylated state is directed by a unique acyl transferase system encoded by two noncontiguous staphylococci genes (lnsAB). Since triacylated Lpps stimulate TLR2 more weakly than their diacylated counterparts, Lpp N-acylation is an important TLR2 immunoevasion factor for determining tolerance or nontolerance in niches such as in the skin microbiota. The discovery of the LnsAB system expands the known diversity of Lpp biosynthesis pathways and acyl transfer biochemistry in bacteria, advances our understanding of Lpp structural heterogeneity, and helps differentiate commensal and noncommensal microbiota.
format article
author John H. Gardiner
Gloria Komazin
Miki Matsuo
Kaitlin Cole
Friedrich Götz
Timothy C. Meredith
author_facet John H. Gardiner
Gloria Komazin
Miki Matsuo
Kaitlin Cole
Friedrich Götz
Timothy C. Meredith
author_sort John H. Gardiner
title Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System
title_short Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System
title_full Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System
title_fullStr Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System
title_full_unstemmed Lipoprotein <italic toggle="yes">N</italic>-Acylation in <italic toggle="yes">Staphylococcus aureus</italic> Is Catalyzed by a Two-Component Acyl Transferase System
title_sort lipoprotein <italic toggle="yes">n</italic>-acylation in <italic toggle="yes">staphylococcus aureus</italic> is catalyzed by a two-component acyl transferase system
publisher American Society for Microbiology
publishDate 2020
url https://doaj.org/article/0dc2e21b11354398ab1fff8f78158146
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