Cysteine string proteins

Gundersen, Cameron B.

doi:10.1016/j.pneurobio.2020.101758

Cited by 12 publications

(13 citation statements)

References 257 publications

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“…DNAJC5 is a ubiquitous cytoplasmic protein located at the surface of late endosomes (LEs). It functions as a co-chaperone in association with Hsc70 or Hsp70, which play a central role in protein homeostasis 22 – 24 . DNAJC5 is also required for an unconventional protein secretion pathway 25 , 26 , recently described as Misfolding-Associated Protein Secretion (MAPS) 27 .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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Pseudomonas aeruginosa can cause nosocomial infections, especially in ventilated or cystic fibrosis patients. Highly pathogenic isolates express the phospholipase ExoU, an effector of the type III secretion system that acts on plasma membrane lipids, causing membrane rupture and host cell necrosis. Here, we use a genome-wide screen to discover that ExoU requires DNAJC5, a host chaperone, for its necrotic activity. DNAJC5 is known to participate in an unconventional secretory pathway for misfolded proteins involving anterograde vesicular trafficking. We show that DNAJC5-deficient human cells, or Drosophila flies knocked-down for the DNAJC5 orthologue, are largely resistant to ExoU-dependent virulence. ExoU colocalizes with DNAJC5-positive vesicles in the host cytoplasm. DNAJC5 mutations preventing vesicle trafficking (previously identified in adult neuronal ceroid lipofuscinosis, a human congenital disease) inhibit ExoU-dependent cell lysis. Our results suggest that, once injected into the host cytoplasm, ExoU docks to DNAJC5-positive secretory vesicles to reach the plasma membrane, where it can exert its phospholipase activity

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Section: Resultsmentioning

confidence: 99%

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

et al. 2021

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“…DNAJC5 is a ubiquitous cytoplasmic protein located at the surface of late endosomes (LEs). It functions as a co-chaperone in association with Hsc70 or Hsp70, which play a central role in protein homeostasis 22–24 . DNAJC5 is also required for an unconventional protein secretion pathway 25,26 , recently described as Misfolded-Associated Protein Secretion (MAPS) 27 .…”

Section: Resultsmentioning

confidence: 99%

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

Deruelle

Bouillot

Job

et al. 2020

Preprint

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Pseudomonas aeruginosa is a causative agent in nosocomial infections, notably in ventilated or cystic fibrosis patients. P. aeruginosa isolates expressing the phospholipase ExoU, an effector of the type III secretion system, are the most pathogenic in clinics. Here, using a genome-wide screen, we discovered that ExoU toxicity requires DNAJC5, a host chaperone, to exert its necrotic activity. DNAJC5 is involved in an unconventional secretory pathway for misfolded proteins involving anterograde vesicular trafficking. DNAJC5-deficient human cells or Drosophila flies knocked-down for the DNAJC5 orthologue were largely resistant to ExoU virulence. ExoU colocalized with DNAJC5-positive vesicles in the host cytoplasm. DNAJC5 mutations preventing vesicle trafficking - identified in adult neuronal ceroid lipofuscinosis, a human congenital disease - inhibited ExoU-dependent cell lysis. These results suggest that, once injected into the host cytoplasm, ExoU docks to DNAJC5-positive secretory vesicles to reach the plasma membrane, where its phospholipase activity is triggered by binding to PI(4,5)P2.

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“…Even though CSP was discovered more than 20 years ago, most published research focuses on CSP’s role in neurodegenerative diseases (reviewed in (Gundersen, 2020)). Nevertheless, little is known about its role in acrosomal exocytosis and its fertility implications.…”

Section: Discussionmentioning

confidence: 99%

“…A neglected area in acrosomal exocytosis is understanding the protein interactions between CSP and SNAREs and accessory proteins to the SNARE assembly process. Previous work in several cellular models shows that CSP interacts with synaptotagmin 9 and the SNARE proteins SNAP-25, synaptobrevin-2, and syntaxin 1 (reviewed in (Gundersen, 2020)). Additional studies are needed to elucidate the precise mechanism by which CSPβ fine-tune acrosomal exocytosis in human sperm.…”

Section: Discussionmentioning

confidence: 99%

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The molecular chaperone Cysteine String Protein is required to stabilize trans-SNARE complexes during human sperm acrosomal exocytosis

Montero

Berberián

Mayorga

et al. 2022

Preprint

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Membrane fusion in sperm cells is crucial for acrosomal exocytosis and must be preserved to assure fertilizing capacity. Evolutionarily conserved protein machinery regulates acrosomal exocytosis. Molecular chaperones play a vital role in spermatogenesis and post-testicular maturation. Cysteine String Protein (CSP) is a member of the Hsp40 co-chaperones, and for more than 20 years, most research published focused on CSP’s role in synapsis. However, the participation of molecular chaperones in acrosomal exocytosis is poorly understood. Using western blot and indirect immunofluorescence, we showed that CSP is present in human sperm, is predominantly bound to membranes, and is palmitoylated. Moreover, using electron microscopy and functional assays, we reported that sequestration of CSP avoided the assembly of trans-complexes and inhibited exocytosis. In summary, our data demonstrated that CSP is necessary and mediates the trans-SNARE complex assembly between the outer acrosomal and plasma membranes, thereby regulating human sperm acrosomal exocytosis. Understanding CSP’s role is critical in identifying new biomarkers and generating new rational-based approaches to treating male infertility.Summary statementCysteine String Protein is necessary and mediates the trans-SNARE complex assembly between the outer acrosomal and plasma membranes, thereby regulating human sperm acrosomal exocytosis.

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Cysteine string proteins

Cited by 12 publications

References 257 publications

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

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

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

The molecular chaperone Cysteine String Protein is required to stabilize trans-SNARE complexes during human sperm acrosomal exocytosis

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