Year: 2024
Type: article
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.
Source: Communications Biology
Institutions: University of Bern, Casma Therapeutics (United States), The University of Melbourne, Walter and Eliza Hall Institute of Medical Research, Monash University, Telethon Institute Of Genetics And Medicine, Baylor College of Medicine, Federico II University Hospital, Texas Children's Hospital, University of Naples Federico II
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,890
OpenAlex ID: W4404581536