Plasmodium berghei Liver Stage Parasites Exploit Host GABARAP Proteins for TFEB Activation

Authors

Jacqueline Schmuckli-Maurer
Annina F Bindschedler
Rahel Wacker
Oliver M Würgler
Ruth Rehmann
Timothy Lehmberg
Leon O Murphy
Thanh N Nguyen
Michael Lazarou
Jlenia Monfregola
Andrea Ballabio
Volker T Heussler

Publication Date

11-21-2024

Journal

Communications Biology

DOI

10.1038/s42003-024-07242-x

PMID

39572689

PMCID

PMC11582615

PubMedCentral® Posted Date

11-21-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Plasmodium berghei, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Animals, Humans, Liver, Autophagy, Malaria, Mice, Microtubule-Associated Proteins, Apoptosis Regulatory Proteins, Adaptor Proteins, Signal Transducing, Host-Parasite Interactions, Hepatocytes, Autophagy, Malaria

Abstract

Plasmodium, the causative agent of malaria, infects hepatocytes prior to establishing a symptomatic blood stage infection. During this liver stage development, parasites reside in a parasitophorous vacuole (PV), whose membrane acts as the critical interface between the parasite and the host cell. It is well-established that host cell autophagy-related processes significantly impact the development of Plasmodium liver stages. Expression of genes related to autophagy and lysosomal biogenesis is orchestrated by transcription factor EB (TFEB). In this study, we explored the activation of host cell TFEB in Plasmodium berghei-infected cells during the liver stage of the parasite. Our results unveiled a critical role of proteins belonging to the Gamma-aminobutyric acid receptor-associated protein subfamily (GABARAP) of ATG8 proteins (GABARAP/L1/L2 and LC3A/B/C) in recruiting the TFEB-blocking FLCN-FNIP (Folliculin-Folliculin-interacting protein) complex to the PVM. Remarkably, the sequestration of FLCN-FNIP resulted in a robust activation of TFEB, reliant on conjugation of ATG8 proteins to single membranes (CASM) and GABARAP proteins. Our findings provide novel mechanistic insights into host cell signaling occurring at the PVM, shedding light on the complex interplay between Plasmodium parasites and the host cell during the liver stage of infection.