The Secrets of Acinetobacter Secretion

Weber, Brent S.; Kinsella, Rachel L.; Harding, Christian M.; Feldman, Mario F.

doi:10.1016/j.tim.2017.01.005

Cited by 67 publications

(67 citation statements)

References 103 publications

(139 reference statements)

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“…In A. baumannii, secretion of proteins from cell surface structures allows the pathogen's interaction with environment and hosts, and hence represents attractive targets for treatment [104,105]. The trimeric autotransporter (Ata) was the first secretion system described in A. baumannii.…”

Section: Protein Secretion Systemsmentioning

confidence: 99%

“…The trimeric autotransporter (Ata) was the first secretion system described in A. baumannii. Ata mediates attachment to human matrix components, particularly collagen, and it is also implicated in biofilm formation/maintenance and virulence [104]. A. baumannii also uses a type II secretion system (T2SS) to export multiple effector proteins.…”

Section: Protein Secretion Systemsmentioning

confidence: 99%

“…A single, conserved, genetic locus encodes 13 core structural proteins of this system, while additional, accessory, or regulatory elements may co-exist. Assembled T6SS system contracts to allow release of the effector protein, which typically targets other bacteria without self-intoxication [104]. In A. baumannii, T6SS may attack other bacteria, where it produces toxins like nucleases, peptidoglycan hydrolases, or cell-membrane active toxins [109].…”

Section: Protein Secretion Systemsmentioning

confidence: 99%

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Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

2020

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Being a multidrug-resistant and an invasive pathogen, Acinetobacter baumannii is one of the major causes of nosocomial infections in the current healthcare system. It has been recognized as an agent of pneumonia, septicemia, meningitis, urinary tract and wound infections, and is associated with high mortality. Pathogenesis in A. baumannii infections is an outcome of multiple virulence factors, including porins, capsules, and cell wall lipopolysaccharide, enzymes, biofilm production, motility, and iron-acquisition systems, among others. Such virulence factors help the organism to resist stressful environmental conditions and enable development of severe infections. Parallel to increased prevalence of infections caused by A. baumannii, challenging and diverse resistance mechanisms in this pathogen are well recognized, with major classes of antibiotics becoming minimally effective. Through a wide array of antibiotic-hydrolyzing enzymes, efflux pump changes, impermeability, and antibiotic target mutations, A. baumannii models a unique ability to maintain a multidrug-resistant phenotype, further complicating treatment. Understanding mechanisms behind diseases, virulence, and resistance acquisition are central to infectious disease knowledge about A. baumannii. The aims of this review are to highlight infections and disease-producing factors in A. baumannii and to touch base on mechanisms of resistance to various antibiotic classes.

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Section: Protein Secretion Systemsmentioning

confidence: 99%

Section: Protein Secretion Systemsmentioning

confidence: 99%

Section: Protein Secretion Systemsmentioning

confidence: 99%

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Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

2020

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“…CpaA was shown previously to be a secreted metallo-endopeptidase with the ability to degrade human Factor V and thus deregulate blood coagulation (29). One possibility is that this interaction inactivates CpaA, preventing self-intoxication of the cell by the proteolytic activity of CpaA (40). To explore the possibility that CpaB is an immunity protein, we compared the proteolytic activity of CpaA alone and in complex with the soluble version of CpaB against human Factor V.…”

Section: Cpab Interaction With Cpaa Does Not Completely Abolish Protementioning

confidence: 99%

Defining the interaction of the protease CpaA with its type II secretion chaperone CpaB and its contribution to virulence in Acinetobacter species

Kinsella

Lopez

Palmer

et al. 2017

Journal of Biological Chemistry

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, , and are a frequent cause of multidrug-resistant, healthcare-associated infections. Our previous work demonstrated that M2 possesses a functional type II secretion system (T2SS) that is required for full virulence. Further, we identified the metallo-endopeptidase CpaA, which has been shown previously to cleave human Factor V and deregulate blood coagulation, as the most abundant type II secreted effector protein. We also demonstrated that its secretion is dependent on CpaB, a membrane-bound chaperone. In this study, we show that CpaA expression and secretion are conserved across several medically relevant species. Additionally, we demonstrate that deletion of results in attenuation of M2 virulence in moth and mouse models. The virulence defects resulting from the deletion of were comparable with those observed upon abrogation of T2SS activity. The virulence defects resulting from the deletion of are comparable with those observed upon abrogation of T2SS activity. We also show that CpaA and CpaB strongly interact, forming a complex in a 1:1 ratio. Interestingly, deletion of the N-terminal transmembrane domain of CpaB results in robust secretion of CpaA and CpaB, indicating that the transmembrane domain is dispensable for CpaA secretion and likely functions to retain CpaB inside the cell. Limited proteolysis of spheroplasts revealed that the C-terminal domain of CpaB is exposed to the periplasm, suggesting that this is the site where CpaA and CpaB interact Last, we show that CpaB does not abolish the proteolytic activity of CpaA against human Factor V. We conclude that CpaA is, to the best of our knowledge, the first characterized, virulence factor secreted by species.

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“…The T2SS is a trans-envelope machine that mediates the transport of effector proteins from the periplasm to the extracellular milieu. First, T2SS effectors are translocated to the periplasmic space by either the general secretory pathway or the twinarginine (TAT) system (5). Once in the periplasm, the effectors fold into their tertiary/quaternary structure, a process occasionally facilitated by dedicated chaperones, and are subsequently targeted to the T2SS machinery for secretion (7).…”

Section: Introductionmentioning

confidence: 99%

The glycoprotease CpaA secreted by medically relevantAcinetobacterspecies targets multipleO-linked host glycoproteins

Haurat

Scott

Venanzio

et al. 2020

Preprint

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Glycans decorate proteins and affect their biological function, including protection against proteolytic degradation. However, pathogenic, and commensal bacteria have evolved specific glycoproteases that overcome the steric impediment posed by carbohydrates, cleaving glycoproteins precisely at their glycosylation site(s). Medically relevant Acinetobacter strains employ their type II secretion system (T2SS) to secrete the glycoprotease CpaA, which contributes to virulence. Previously, CpaA was shown to cleave two O-linked glycoproteins, factors V and XII, leading to reduced blood coagulation. In this work, we show that CpaA cleaves a broader range of O-linked human glycoproteins, including several glycoproteins involved in complement activation, such as CD55 and CD46. However, only CD55 was removed from the cell surface, while CD46 remained unaltered during the A. nosocomialis infection assay. We show that CpaA has a unique consensus target sequence that consists of a glycosylated serine or threonine residue after a proline residue (P-S/T), and its activity is not affected by sialic acids. Molecular modeling and mutagenesis analysis of CpaA suggest that the indole ring of Trp493 and the ring of the Pro residue in the substrate form a key interaction that contributes to CpaA sequence selectivity. Similar bacterial glycoproteases have recently gained attention as tools for proteomic analysis of human glycoproteins, and CpaA appears to be a robust and attractive new component of the glycoproteomics toolbox. Combined, our work provides insight into the function and possible application of CpaA, a member of a widespread class of broad-spectrum bacterial glycoproteases involved in host-pathogen interactions.IMPORTANCECpaA is a glycoprotease expressed by members of the Acinetobacter baumannii-calcoaceticus complex and it is the first bona fide secreted virulence factor identified in these species. Here, we show that CpaA cleaves multiple targets precisely at O-glycosylation sites preceded by a Pro residue. This feature, together with the observation that sialic acid does not impact CpaA activity, makes of this enzyme an attractive tool for the analysis of O-linked human protein for biotechnical and diagnostic purposes. Previous work identified proteins involved in blood coagulation as targets of CpaA. Our work broadens the set of targets of CpaA, pointing towards additional roles in bacteria-host interactions. We propose that CpaA belongs to an expanding class of functionally-defined glycoproteases that targets multiple O-linked host glycoproteins.

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The Secrets of Acinetobacter Secretion

Cited by 67 publications

References 103 publications

Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

Insights into Acinetobacter baumannii: A Review of Microbiological, Virulence, and Resistance Traits in a Threatening Nosocomial Pathogen

Defining the interaction of the protease CpaA with its type II secretion chaperone CpaB and its contribution to virulence in Acinetobacter species

The glycoprotease CpaA secreted by medically relevantAcinetobacterspecies targets multipleO-linked host glycoproteins

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