The Consistent Tick-Vertebrate Infectious Cycle of the Lyme Disease Spirochete Enables Borrelia burgdorferi To Control Protein Expression by Monitoring Its Physiological Status

Stevenson, Brian; Krusenstjerna, Andrew C.; Castro-Padovani, Tatiana N.; Savage, Christina R.; Jutras, Brandon L.; Saylor, Timothy C.

doi:10.1128/jb.00606-21

Cited by 13 publications

(17 citation statements)

References 186 publications

(197 reference statements)

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“…Genes encoding Elps are located on 32-kilobase circular plasmids (i.e. cp32 genetic elements) and are expressed during the mammalian phase of infection, suggesting a potential role in host interaction, which is further supported by the identification of laminin as a binding partner for ErpX/ElpX (35)(36)(37)(38)(39). We showed that ElpB and ElpQ bound with high affinity to the CP proteases C1r and C1s and were selective for the activated forms of each protease (31).…”

Section: Introductionmentioning

confidence: 71%

Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s

Garrigues

Thomas

Leong

et al. 2022

Preprint

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Proteolytic cascades comprise several important physiological systems, including a primary arm of innate immunity called the complement cascade. To safeguard against complement-mediated attack, the etiologic agent of Lyme disease, Borreliella burgdorferi, produces numerous outer surface-localized lipoproteins that contribute to successful complement evasion. Recently, we discovered a pair of B. burgdorferi surface lipoproteins of the OspEF-related protein family – termed ElpB and ElpQ – that inhibit antibody-mediated complement activation. In this study, we investigate the molecular mechanism of ElpB and ElpQ complement inhibition using an array of biochemical and biophysical approaches. In vitro assays of complement activation show that an independently folded homologous C-terminal domain of each Elp protein maintains full complement inhibitory activity and selectively inhibits the classical pathway. Using surface plasmon resonance, Alpha bead-based technology, and C1s enzyme assays, we show that binding of Elp proteins to activated C1s blocks C4 cleavage by competing with C1s/C4 binding without occluding the active site. C1s-mediated C4 cleavage is dependent on activation-induced binding sites, termed exosites. To test whether these exosites are involved in Elp/C1s binding, we performed site-directed mutagenesis which showed that ElpB– and ElpQ-binding require C1s residues in the anion-binding exosite located on the serine protease domain of C1s. Based on these results, we propose a model whereby ElpB and ElpQ exploit activation-induced conformational changes that are normally important for C1s-mediated C4 cleavage. Our study expands the known complement evasion mechanisms of microbial pathogens and reveals a novel molecular mechanism for selective C1s inhibition by Lyme disease spirochetes.

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Section: Introductionmentioning

confidence: 71%

Outer surface lipoproteins from the Lyme disease spirochete exploit the molecular switch mechanism of the complement protease C1s

Garrigues

Thomas

Leong

et al. 2022

Preprint

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“…In this bacterium, the operon dnaX-ebfC is regulated by a promoter located upstream of dnaX [ 30 ]. In addition, ebfC can also be expressed by a promoter located in the dnaX structural sequence, as determined by RT-PCR and GFP-transcriptional fusions [ 30 , 38 ]. In addition, DnaA, one of the main proteins of chromosomal replication, has been suggested to be involved in the regulation of expression of the dnaX - ebfC operon in B. burgdorferi, as discussed by Stevenson et al [ 38 ].…”

Section: Operon Structure and Expressionmentioning

confidence: 99%

“…Cp32s, one of these elements, is circular and presents characteristics of a bacteriophage genome [ 57 ]. Among other traits, Cp32s contain genes that encode a polymorphic family of surface lipoproteins, the Erp proteins, involved in pathogenesis by promoting binding to plasminogen, laminin, and complement factor H, thus conferring adhesion to host tissues and inhibiting complement activation [ 38 ]. EbfC was found to regulate the transcription of erp operons by binding to operator sequences in the promoter region of erp genes.…”

Section: Ebfc/ybab Has Important Biological Functionsmentioning

confidence: 99%

“…This protein binds cooperatively to the erp operator, thereby blocking the binding of RNApol to the promoter. This repression is enhanced by the binding of BpuR ( b orrelial PUR domain), another DNA-binding protein [ 38 , 58 ]. EbfC functions as an anti-repressor of erp operons and competes with BpaB to bind to the regulatory region, thus stimulating the transcription of erp genes [ 31 , 38 ].…”

Section: Ebfc/ybab Has Important Biological Functionsmentioning

confidence: 99%

“…This repression is enhanced by the binding of BpuR ( b orrelial PUR domain), another DNA-binding protein [ 38 , 58 ]. EbfC functions as an anti-repressor of erp operons and competes with BpaB to bind to the regulatory region, thus stimulating the transcription of erp genes [ 31 , 38 ]. ebfC exhibited a higher transcription level during the exponential growth phase than during the stationary phase, where transcripts were not detected.…”

Section: Ebfc/ybab Has Important Biological Functionsmentioning

confidence: 99%

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EbfC/YbaB: A Widely Distributed Nucleoid-Associated Protein in Prokaryotes

et al. 2022

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Genomic compaction is an essential characteristic of living organisms. Nucleoid-associated proteins (NAPs) are a group of small proteins that play crucial roles in chromosome architecture and affect DNA replication, transcription, and recombination by imposing topological alterations in genomic DNA, thereby modulating global gene expression. EbfC/YbaB was first described as a DNA-binding protein of Borrelia burgdorferi that regulates the expression of surface lipoproteins with roles in virulence. Further studies indicated that this protein binds specifically and non-specifically to DNA and colocalises with nucleoids in this bacterium. The data showed that this protein binds to DNA as a homodimer, although it can form other organised structures. Crystallography analysis indicated that the protein possesses domains responsible for protein–protein interactions and forms a “tweezer” structure probably involved in DNA binding. Moreover, sequence analysis revealed conserved motifs that may be associated with dimerisation. Structural analysis also showed that the tridimensional structure of EbfC/YbaB is highly conserved within the bacterial domain. The DNA-binding activity was observed in different bacterial species, suggesting that this protein can protect DNA during stress conditions. These findings indicate that EbfC/YbaB is a broadly distributed NAP. Here, we present a review of the existing data on this NAP.

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