The <scp>HtrA</scp> protease of <i><scp>B</scp>orrelia burgdorferi</i> degrades outer membrane protein <scp>BmpD</scp> and chemotaxis phosphatase <scp>CheX</scp>

Coleman, James L.; Crowley, Jameson T.; Toledo, Álvaro; Benach, Jorge L.

doi:10.1111/mmi.12213

Cited by 46 publications

(87 citation statements)

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“…The primary sequence of BbHtrA, which possesses typical serine protease activity (28)(29)(30)(31)(32), is highly conserved within diverse B. burgdorferi sensu lato strains. To further confirm the conservation of BbHtrA and to assess whether diverse isolates and strains of the species B. burgdorferi sensu lato produce HtrA orthologs, whole-cell lysates from different strains were probed with BbHtrA antibody raised against isolate B31.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, the genome of B. burgdorferi contains a single htrA gene (locus bb0104) (28) that encodes BbHtrA, which has been biochemically characterized and shown to possess conserved, catalytic, serine-dependent proteolytic activity (28)(29)(30)(31)(32). BbHtrA possesses an N-terminal signal peptide sequence, and apart from its periplasmic and cytosolic fractions, it also localizes in outer membrane vesicles and is secreted into growth media (29,32). Few interacting partners and substrates of BbHtrA have also been identified (28)(29)(30)(31)(32).…”

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confidence: 99%

“…BbHtrA possesses an N-terminal signal peptide sequence, and apart from its periplasmic and cytosolic fractions, it also localizes in outer membrane vesicles and is secreted into growth media (29,32). Few interacting partners and substrates of BbHtrA have also been identified (28)(29)(30)(31)(32). For instance, BbHtrA has been shown to cleave basic membrane protein D (BmpD) and chemotaxis signal transduction phosphatase (CheX) (29).…”

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confidence: 99%

“…Few interacting partners and substrates of BbHtrA have also been identified (28)(29)(30)(31)(32). For instance, BbHtrA has been shown to cleave basic membrane protein D (BmpD) and chemotaxis signal transduction phosphatase (CheX) (29). In addition, previous in vitro studies have suggested that BbHtrA also cleaves BB0323 (28), a borrelial protein important for cell growth, fission, and infection (33,34).…”

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confidence: 99%

“…Also, it has been shown that BbHtrA degrades the extracellular matrix proteoglycan aggrecan, fibronectin, and numerous other proteoglycans (32), and recently, the inhibition of this protease by zinc has been reported (35). However, despite these seminal studies, the precise biological significance of BbHtrA remains enigmatic, as efforts aimed at targeted deletion of the gene have thus far not been successful (28)(29)(30). Here we report the successful generation and characterization of a BbhtrA deletion mutant and complemented isolates of an infectious isolate of B. burgdorferi, which highlight a critical role for this protease in spirochete biology and infectivity.…”

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HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

Sharma

Thakur

et al. 2016

Infect Immun

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d High-temperature requirement protease A (HtrA) represents a family of serine proteases that play important roles in microbial biology. Unlike the genomes of most organisms, that of Borrelia burgdorferi notably encodes a single HtrA gene product, termed BbHtrA. Previous studies identified a few substrates of BbHtrA; however, their physiological relevance could not be ascertained, as targeted deletion of the gene has not been successful. Here we show that BbhtrA transcripts are induced during spirochete growth either in the stationary phase or at elevated temperature. Successful generation of a BbhtrA deletion mutant and restoration by genetic complementation suggest a nonessential role for this protease in microbial viability; however, its remarkable growth, morphological, and structural defects during cultivation at 37°C confirm a high-temperature requirement for protease activation and function. The BbhtrA-deficient spirochetes were unable to establish infection of mice, as evidenced by assessment of culture, PCR, and serology. We show that transcript abundance as well as proteolytic processing of a borrelial protein required for cell fission and infectivity, BB0323, is impaired in BbhtrA mutants grown at 37°C, which likely contributed to their inability to survive in a mammalian host. Together, these results demonstrate the physiological relevance of a unique temperature-regulated borrelial protease, BbHtrA, which further enlightens our knowledge of intriguing aspects of spirochete biology and infectivity. L yme disease is a common vector-borne infectious disease in the Northern Hemisphere, posing a serious health threat to humans and animals (1-3). Newly revised estimates from the Centers for Disease Control and Prevention suggest that there are likely to be over 300,000 new cases per year in the United States alone, and a vaccine to prevent human infection is currently unavailable. The disease can be transmitted via the bite of the infected arthropod vector, the Ixodes scapularis tick, harboring the spirochete pathogen Borrelia burgdorferi, often resulting in serious illness in susceptible hosts (2, 3). While most Lyme disease cases can be treated with an antibiotic, a minority of patients will have persistent or relapsing nonobjective symptoms that vary in intensity, are nonresponsive to further antibiotic therapy, and are collectively termed chronic Lyme disease or posttreatment Lyme disease syndrome, the underlying mechanism and pathogenesis of which remain highly controversial (4). Detection of early Lyme disease, when antibiotic treatment is most effective, also remains challenging, as the infection reflects many nonspecific symptoms that are shared by many other febrile or influenza-like diseases (5, 6). Thus, the development of efficient diagnostics, vaccines, or new effective drugs is a high-priority goal that requires a thorough understanding of the unusual biology and infection process of this pathogen.The pathogen of Lyme disease exhibits evolutionary divergence from other bacteria, even related...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

Sharma

Thakur

et al. 2016

Infect Immun

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The lipid raft proteome ofBorrelia burgdorferi

et al. 2015

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Eukaryotic lipid rafts are membrane microdomains that have significant amounts of cholesterol and a selective set of proteins that have been associated with multiple biological functions. The Lyme disease agent, Borrelia burgdorferi, is one of an increasing number of bacterial pathogens that incorporates cholesterol onto its membrane, and form cholesterol glycolipid domains that possess all the hallmarks of eukaryotic lipid rafts. In this study, we isolated lipid rafts from cultured B. burgdorferi as a detergent resistant membrane (DRM) fraction on density gradients, and characterized those molecules that partitioned exclusively or are highly enriched in these domains. Cholesterol glycolipids, the previously known raft-associated lipoproteins OspA and OpsB, and cholera toxin partitioned into the lipid rafts fraction indicating compatibility with components of the DRM. The proteome of lipid rafts was analyzed by a combination of LC-MS/MS or MudPIT. Identified proteins were analyzed in silico for parameters that included localization, isoelectric point, molecular mass and biological function. The proteome provided a consistent pattern of lipoproteins, proteases and their substrates, sensing molecules and prokaryotic homologs of eukaryotic lipid rafts. This study provides the first analysis of a prokaryotic lipid raft and has relevance for the biology of Borrelia, other pathogenic bacteria, as well as for the evolution of these structures. All MS data have been deposited in the ProteomeXchange with identifier PXD002365 (http://proteomecentral.proteomexchange.org/dataset/PXD002365).

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Borrelia burgdorferi and other Borrelia species

Wang

2024

Molecular Medical Microbiology

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The HtrA protease of Borrelia burgdorferi degrades outer membrane protein BmpD and chemotaxis phosphatase CheX

Cited by 46 publications

References 81 publications

HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

HtrA, a Temperature- and Stationary Phase-Activated Protease Involved in Maturation of a Key Microbial Virulence Determinant, Facilitates Borrelia burgdorferi Infection in Mammalian Hosts

The lipid raft proteome ofBorrelia burgdorferi

Borrelia burgdorferi and other Borrelia species

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