The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis

Deruelle, Vincent; Bouillot, Stéphanie; Job, Viviana; Taillebourg, Emmanuel; Fauvarque, Marie-Odile; Attrée, Ina; Huber, Philippe

doi:10.1038/s41467-021-24337-9

Cited by 13 publications

(16 citation statements)

References 65 publications

(87 reference statements)

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“…3A). Exoenzyme U (ExoU) from Pseudomonas aeruginosa T3SS has phospholipase A 2 activity that cause instant lysis of host cells ( 17 , 18 ), and substantial cell death was observed when cells were treated by PVC with ExoU in the cytotoxicity assays (Fig. 3B and fig.…”

Section: Resultsmentioning

confidence: 99%

N-terminal signal peptides facilitate the engineering of PVC complex as a potent protein delivery system

et al. 2022

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Extracellular contractile injection systems (eCISs) are widespread bacterial nanomachines that resemble T4 phage tail. As a typical eCIS, Photorhabdus virulence cassette (PVC) was proposed to inject toxins into eukaryotic cells by puncturing the cell membrane from outside. This makes it an ideal tool for protein delivery in biomedical research. However, how to manipulate this nanocomplex as a molecular syringe is still undetermined. Here, we identify that one group of N-terminal signal peptide (SP) sequences are crucial for the effector loading into the inner tube of PVC complex. By application of genetic operation, cryo–electron microscopy, in vitro translocation assays, and animal experiments, we show that, under the guidance of the SP, numerous prokaryotic and eukaryotic proteins can be loaded into PVC to exert their functions across cell membranes. We therefore might customize PVC as a potent protein delivery nanosyringe for biotherapy by selecting cargo proteins in a broad spectrum, regardless of their species, sizes, and charges.

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Section: Resultsmentioning

confidence: 99%

N-terminal signal peptides facilitate the engineering of PVC complex as a potent protein delivery system

et al. 2022

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“…ExoU utilizes the chaperone protein called SpcU for secretion through the T3SS [311]. ExoU also requires host DNAJC5 chaperone and ubiquitin as the cofactor for its activity within the target host cell [253][254][255][312][313][314]. The MLD (membrane localization domain) of ExoU has been mapped to residues 550-687 in its C-terminal domain [315].…”

Section: Exoumentioning

confidence: 99%

Pseudomonas aeruginosa Cytotoxins: Mechanisms of Cytotoxicity and Impact on Inflammatory Responses

Wood

Goldufsky

Seu

et al. 2023

Cells

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Pseudomonas aeruginosa is one of the most virulent opportunistic Gram-negative bacterial pathogens in humans. It causes many acute and chronic infections with morbidity and mortality rates as high as 40%. P. aeruginosa owes its pathogenic versatility to a large arsenal of cell-associated and secreted virulence factors which enable this pathogen to colonize various niches within hosts and protect it from host innate immune defenses. Induction of cytotoxicity in target host cells is a major virulence strategy for P. aeruginosa during the course of infection. P. aeruginosa has invested heavily in this strategy, as manifested by a plethora of cytotoxins that can induce various forms of cell death in target host cells. In this review, we provide an in-depth review of P. aeruginosa cytotoxins based on their mechanisms of cytotoxicity and the possible consequences of their cytotoxicity on host immune responses.

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“…Quercetin is a plant-derived flavonoid that has previously been shown to inhibit DNAJC5-mediated trafficking of a bacterial toxin ( Figure 1—figure supplement 3D ; Deruelle et al, 2021 ). We found that quercetin also inhibited Nluc-α-syn secretion in a dose-dependent manner ( Figure 1—figure supplement 3E ), implying a role for endogenous DNAJC5 in α-syn secretion.…”

Section: Resultsmentioning

confidence: 99%

Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers

Villegas

Sirkis

et al. 2023

eLife

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Alpha-synuclein (α-syn), a major component of Lewy bodies found in Parkinson's disease (PD) patients, has been found exported outside of cells and may mediate its toxicity via cell-to-cell transmission. Here, we reconstituted soluble, monomeric a-syn secretion by the expression of DnaJ homolog subfamily C member 5 (DNAJC5) in HEK293T cells. DNAJC5 undergoes palmitoylation and anchors on the membrane. Palmitoylation is essential for DNAJC5-induced α-syn secretion, and the secretion is not limited by substrate size or unfolding. Cytosolic α-syn is actively translocated and sequestered in an endosomal membrane compartment in a DNAJC5-dependent manner. Reduction of α-syn secretion caused by a palmitoylation-deficient mutation in DNAJC5 can be reversed by a membrane-targeting peptide fusion-induced oligomerization of DNAJC5. The secretion of endogenous α-syn mediated by DNAJC5 is also found in a human neuroblastoma cell line, SH-SY5Y, differentiated into neurons in the presence of retinoic acid, and in human induced pluripotent stem cell-derived midbrain dopamine neurons. We propose that DNAJC5 forms a palmitoylated oligomer to accommodate and export α-syn.

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The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis

Cited by 13 publications

References 65 publications

N-terminal signal peptides facilitate the engineering of PVC complex as a potent protein delivery system

N-terminal signal peptides facilitate the engineering of PVC complex as a potent protein delivery system

Pseudomonas aeruginosa Cytotoxins: Mechanisms of Cytotoxicity and Impact on Inflammatory Responses

Unconventional secretion of α-synuclein mediated by palmitoylated DNAJC5 oligomers

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