Plasmodium UIS3 sequesters host LC3 to avoid elimination by autophagy in hepatocytes

Abstract

The causative agent of malaria, Plasmodium, replicates inside a membrane-bound parasitophorous vacuole (PV) that shields this intracellular parasite from the cytosol of the host cell1. One common threat for intracellular pathogens is the homeostatic process of autophagy through which cells capture unwanted intracellular material for lysosomal degradation2. During the liver stage of a malaria infection, Plasmodium parasites are targeted by the autophagy machinery of the host cell and the PV membrane (PVM) becomes decorated with several autophagy markers, including LC3 (microtubule-associated protein 1 light chain 3)3,4. Here we show that Plasmodium berghei parasites infecting hepatic cells rely on the PVM transmembrane protein UIS3 to avoid elimination by host cell-mediated autophagy. We found that UIS3 binds host LC3 through a non-canonical interaction with a specialised surface on LC3 where host proteins with essential functions during autophagy also bind. UIS3 acts as a bona fide autophagy inhibitor by competing with host LC3-interacting proteins for LC3 binding. Our work identifies UIS3, one of the most promising candidates for a genetically-attenuated vaccine against malaria5, as a unique and potent mediator of autophagy evasion in Plasmodium. We propose that the protein-protein interaction between UIS3 and host LC3 represents a target for antimalarial drug development.

Targeting liver stage malaria with metformin

“…Consistent with our in vitro and in vivo data of reduced intrahepatic schizont size under metformin treatment, a shutdown of a pro-proliferative program within the host cell would limit parasite growth. In addition to suppression of pro-proliferative pathways during liver stage infection, metformin could also promote cell-autonomous host defense mechanisms, such as increased apoptosis, autophagy, lysosome-vacuole fusion, type I interferon signaling, and reactive oxygen species-mediated killing, all of which have been shown to induce parasite killing and clearance of Plasmodium-infected hepatocytes via infiltrating phagocytes (57)(58)(59)(60). Similar metformin-mediated mechanisms have been described for other intracellular pathogens, such as M. tuberculosis (25), Legionella pneumophilia (61), and hepatitis C virus (62).…”

The Irish potato famine pathogen subverts host vesicle trafficking to channel starvation-induced autophagy to the pathogen interface

“…Among the diverse set of potato ATG8 members (Kellner et al, 2017; Zess et al, 2019), PexRD54 preferentially binds the ATG8CL isoform and outcompetes Joka2/NBR1 from ATG8CL complexes, thereby disarming defense-related autophagy at the pathogen interface. Intriguingly, PexRD54 does not fully shutdown autophagy as has been shown for animal pathogens that suppress autophagy (Choy et al, 2012; Kimmey and Stallings, 2016; Real et al, 2017; Xu et al, 2019). Instead, it stimulates formation of autophagosomes that accumulate around the pathogen interface.…”

Plasmodium secretion induces hepatocyte lysosome exocytosis and promotes parasite entry

“…Many intracellular pathogens target and subvert these trafficking events for their own benefit ( 2, 3 ). Previous work has demonstrated that the Plasmodium liver stage PV membrane co-localizes with late endosomes( 4 ), lysosomes( 5 ) and autophagic vesicles( 6 ). When this association is initiated during Plasmodium life-cycle progression remains unknown.…”