A bacterial toxin guided by a human protein

Pseudomonas aeruginosa can cause nosocomial infections via the ExoU toxin, which acts on plasma membrane lipids, causing their rupture and necrosis in the host cell. By discovering that ExoU requires the host DNAJC5 protein for its necrotic activity, IRIG researchers have identified the Achilles heel of this toxin.

Pseudomonas aeruginosa is an opportunistic pathogenic bacterium causing nosocomial acute infections, as well as fatal chronic infections in cystic fibrosis patients. Clinical isolates are frequently multi-resistant to antibiotics, which complicates the management of infected patients. P. aeruginosa possesses an arsenal of virulence factors, the most active of which is an injectisome that injects toxins directly into target cells. ExoU is the most harmful toxin injected by this system. Its necrotizing action is linked to its phospholipase activity (Figure) that causes the rupture of the plasma membrane of the host cell, and results in severe lesions in infected tissues.

To carry out their biological activity, bacterial toxins often hijack molecules or mechanisms of the host cell. IRIG researchers used a genetic screen employing CRISPR-Cas9 technology to search for genes that might be involved in ExoU toxicity. Only one such gene was identified! This gene encodes the human DNAJC5 protein, which is known to play a central role in the secretion of some cytoplasmic proteins via an unconventional vesicular transport system (MAPS). The researchers demonstrated that DNAJC5 guides the toxin to the plasma membrane of the host cell, where ExoU can exert its toxic activity (Figure). They showed that cells deficient in DNAJC5, or Drosophila in which the DNAJC5 gene orthologue was down regulated, are largely resistant to ExoU toxicity.

The transportation system provided by the DNAJC5 protein is thus the Achilles heel of Pseudomonas aeruginosa’s ExoU toxin. This discovery could be used to prevent the devastating action of ExoU in acute P. aeruginosa infections. .

The bacterial toxin ExoU requires a host trafficking chaperone for transportation and to induce necrosis. Deruelle V, Bouillot S, Job V, Taillebourg E, Fauvarque MO, Attrée A and Huber P. Nature Communications, 2021