K63-linked ubiquitination targets Toxoplasma gondii for endo-lysosomal destruction in IFNγ-stimulated human cells
Paper published in PLoS pathogens, January 2016
Publisher: Public Library of Science San Francisco, CA USA
The manuscript by Clough et al. (2016) and other sources reveal that in an immune-stimulated environment, Toxoplasma gondii type II parasites in human cells undergo vacuole fusion with the host endo-lysosomal machinery, leading to parasite death by acidification. This process is dependent on IFNγ and K63-linked ubiquitination of the parasitophorous vacuole (PV), which recruits NDP52 and p62 in overlapping microdomains. Autophagy proteins Atg16L1, GABARAP, and LC3B are recruited to a minor extent, but their role in parasite replication is not significant. The findings suggest that human vacuoles do not rupture, but rather become LAMP1- and LysoTracker-positive, indicating fusion with the endo-lysosomal system. Inhibition of host ubiquitination and endosomal acidification enhances parasite viability under IFNγ-stimulated conditions. The study provides insight into the novel virulence-driven Toxoplasma human host defence pathway. Another study suggests that type II Toxoplasma is eliminated from IFNγ-stimulated human umbilical vein endothelial cells (HUVECs) through an endo-lysosomal destruction pathway that is dependent on ubiquitination and acidification of the vacuole. The findings might uncover novel host and pathogen targets for the development of anti-Toxoplasma compounds.