Self‐immunity to antibacterial peptides by ABC transporters

Smits, Sander H. J.; Schmitt, Lutz; Beis, Konstantinos

doi:10.1002/1873-3468.13953

Cited by 29 publications

(36 citation statements)

References 204 publications

(313 reference statements)

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“…Bacteriocin transport is most often mediated by Type IV-ABC transporters, which are known to expel toxic molecules out of the producing-cells [ 5 , 8 , 10 ]. Interestingly, this type of transporter is also involved in the transport of some LLB, such as aureocin A70 [ 39 ], aureocin A53 [ 16 ], EntD14 [ 21 ], lacticin Q, and lacticin Z [ 40 , 41 ].…”

Section: Discussionmentioning

confidence: 99%

“…The export of bacteriocins is tightly associated with a complex immunity machinery, since the bacteriocin-producing bacteria need to protect themselves from the toxicity of their own bacteriocins. This immunity can be exerted by dedicated proteins and/or ABC transporters [ 10 ]. This is the case of NisEFG for nisin [ 11 ] or As-48EFGH for the cyclic enterocin AS-48 [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

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Evidence for the Involvement of Pleckstrin Homology Domain-Containing Proteins in the Transport of Enterocin DD14 (EntDD14); a Leaderless Two-Peptide Bacteriocin

Pérez-Ramos

Ladjouzi

Benachour

et al. 2021

IJMS

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Bacteriocins synthesis is initiated from an inactive precursor, which is composed of an N-terminal leader peptide attached to a C-terminal pro-peptide. However, leaderless bacteriocins (LLB) do not possess this N-terminal leader peptide nor undergo post-translational modifications. These atypical bacteriocins are observed to be immediately active after their translation in the cytoplasm. However, although considered to be simple, the biosynthetic pathway of LLB remains to be fully understood. Enterocin DD14 (EntDD14) is a two-peptide LLB produced by Enterococcus faecalis 14, which is a strain isolated from meconium. In silico analysis of DNA encoding EntDD14 located a cluster of 10 genes ddABCDEFGHIJ, where ddE and ddF encode the peculiar DdE and DdF proteins, carrying pleckstrin homology (PH) domains. These modules are quite common in Eucarya proteins and are known to be involved in intracellular signaling or cytoskeleton organization. To elucidate their role within the EntDD14 genetic determinants, we constructed deletion mutants of the ddE and ddF genes. As a result, the mutants were unable to export EntDD14 outside of the cytoplasm even though there was a clear expression of structural genes ddAB encoding EntDD14, and genes ddHIJ encoding an ABC transporter. Importantly, in these mutant strains (ΔddE and ΔddF), EntDD14 was detected by mass spectrometry in the intracellular soluble fraction exerting, upon its accumulation, a toxic effect on the producing strain as revealed by cell-counting and confocal microscopy analysis. Taken together, these results clearly indicate that PH domain-containing proteins, such as DdE and DdF, are involved in the transport of the leaderless two-peptide EntDD14.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Evidence for the Involvement of Pleckstrin Homology Domain-Containing Proteins in the Transport of Enterocin DD14 (EntDD14); a Leaderless Two-Peptide Bacteriocin

Pérez-Ramos

Ladjouzi

Benachour

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Bacteriocin transport is most often mediated by Type IV-ABC transporters, which are known to expel toxic molecules out of the producing-cells [5,8,10]. Interestingly, this type of transporter is also involved in the transport of some LLB, like aureocin A70 [15], aureocin A53 [16], EntD14 [19], lacticin Q and lacticin Z [29,30].…”

Section: Discussionmentioning

confidence: 99%

Evidence for a Pleckstrin Homology Domain-containing Proteins as Novel Class of Leaderless Bacteriocins Transporters

Pérez-Ramos

Benachour

Drider

2021

Preprint

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Bacteriocins biosynthetic pathway is initiated from an inactive precursor, which is composed of an N-terminal leader peptide attached to a C-terminal pro-peptide. However, leaderless bacteriocins (LLB) do not possess this N-terminal leader peptide, nor undergo post-translational modifications. These atypical bacteriocins are observed to be immediately active after their translation in the cytoplasm. However, although considered to be simple, the biosynthetic pathway of LLB remains to be fully understood. Enterocin DD14 (EntDD14) is a two-peptide LLB produced by Enterococcus faecalis 14, a strain isolated from meconium. In silico analysis of DNA encoding EntDD14 located a cluster of 10 genes ddABCDEFGHIJ, where ddE and ddF encode the peculiar DdE and DdF proteins, carrying pleckstrin homology (PH) domains. These modules are quite common in Eucarya proteins and are known to be involved in intracellular signalling or cytoskeleton organization. To elucidate their role within the EntDD14 genetic determinant, we constructed deletion mutants of the 2 corresponding genes. As a result, the ddE or ddF mutants are unable to externalize EntDD14 outside of the cytoplasm, even though there was clear expression of structural genes ddAB encoding EntDD14, and genes ddHIJ encoding an ABC transporter. Importantly, in these mutant strains (DddE and DddF), EntDD14 was detected by mass spectrometry in the intracellular soluble fraction exerting, upon its accumulation, a toxic effect on the producing strain as revealed by cell-counting and confocal microscopy analysis. Taken together, these results clearly indicate that PH domain-containing proteins, like DdE and DdF, are acting as transporters of the leaderless two-peptide EntDD14.

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“…All are highly conserved in non-pathogenic yeasts ( Table 1 ). Their overexpression in pathogens causes hallmark MDR phenotypes seen for mammalian or bacterial ABC transporters [ 111 , 141 , 217 , 218 , 235 , 261 , 262 , 263 , 264 ].…”

Section: Introductionmentioning

confidence: 99%

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

Khunweeraphong

Kuchler

2021

IJMS

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Multidrug resistance (MDR) can be a serious complication for the treatment of cancer as well as for microbial and parasitic infections. Dysregulated overexpression of several members of the ATP-binding cassette transporter families have been intimately linked to MDR phenomena. Three paradigm ABC transporter members, ABCB1 (P-gp), ABCC1 (MRP1) and ABCG2 (BCRP) appear to act as brothers in arms in promoting or causing MDR in a variety of therapeutic cancer settings. However, their molecular mechanisms of action, the basis for their broad and overlapping substrate selectivity, remains ill-posed. The rapidly increasing numbers of high-resolution atomic structures from X-ray crystallography or cryo-EM of mammalian ABC multidrug transporters initiated a new era towards a better understanding of structure–function relationships, and for the dynamics and mechanisms driving their transport cycles. In addition, the atomic structures offered new evolutionary perspectives in cases where transport systems have been structurally conserved from bacteria to humans, including the pleiotropic drug resistance (PDR) family in fungal pathogens for which high resolution structures are as yet unavailable. In this review, we will focus the discussion on comparative mechanisms of mammalian ABCG and fungal PDR transporters, owing to their close evolutionary relationships. In fact, the atomic structures of ABCG2 offer excellent models for a better understanding of fungal PDR transporters. Based on comparative structural models of ABCG transporters and fungal PDRs, we propose closely related or even conserved catalytic cycles, thus offering new therapeutic perspectives for preventing MDR in infectious disease settings.

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Self‐immunity to antibacterial peptides by ABC transporters

Cited by 29 publications

References 204 publications

Evidence for the Involvement of Pleckstrin Homology Domain-Containing Proteins in the Transport of Enterocin DD14 (EntDD14); a Leaderless Two-Peptide Bacteriocin

Evidence for the Involvement of Pleckstrin Homology Domain-Containing Proteins in the Transport of Enterocin DD14 (EntDD14); a Leaderless Two-Peptide Bacteriocin

Evidence for a Pleckstrin Homology Domain-containing Proteins as Novel Class of Leaderless Bacteriocins Transporters

Multidrug Resistance in Mammals and Fungi—From MDR to PDR: A Rocky Road from Atomic Structures to Transport Mechanisms

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