Toxoplasma gondii exploits the host ESCRT machinery for parasite uptake of host cytosolic proteins

Autor: Yolanda Rivera-Cuevas, Joshua Mayoral, Manlio Di Cristina, Anna-Lisa E. Lawrence, Einar B. Olafsson, Romir K. Patel, Dishari Thornhill, Benjamin S. Waldman, Akira Ono, Jonathan Z. Sexton, Sebastian Lourido, Louis M. Weiss, Vern B. Carruthers
Jazyk: angličtina
Rok vydání: 2021
Předmět:
RNA viruses
Physiology
Cultured tumor cells
Protozoan Proteins
Pathogenesis
Pathology and Laboratory Medicine
Toxoplasma Gondii
Mice
Medical Conditions
Immunodeficiency Viruses
Medicine and Health Sciences
Biology (General)
Protozoans
Ingestion
Eukaryota
Medical Microbiology
Viral Pathogens
Host-Pathogen Interactions
Viruses
Cell lines
Pathogens
Biological cultures
Toxoplasma
Toxoplasmosis
Research Article
QH301-705.5
Immunology
Antigens
Protozoan
macromolecular substances
Transfection
Microbiology
Parasite Replication
Host-Parasite Interactions
Virology
Retroviruses
Genetics
Parasitic Diseases
Animals
Humans
HeLa cells
Molecular Biology Techniques
Microbial Pathogens
Molecular Biology
Endosomal Sorting Complexes Required for Transport
Lentivirus
Organisms
Biology and Life Sciences
HIV
RC581-607
Cell cultures
Parasitic Protozoans
Research and analysis methods
HIV-1
Parasitology
Immunologic diseases. Allergy
Physiological Processes
Zdroj: PLoS Pathogens, Vol 17, Iss 12, p e1010138 (2021)
PLoS Pathogens
ISSN: 1553-7374
1553-7366
Popis: Toxoplasma gondii is a master manipulator capable of effectively siphoning the resources from the host cell for its intracellular subsistence. However, the molecular underpinnings of how the parasite gains resources from its host remain largely unknown. Residing within a non-fusogenic parasitophorous vacuole (PV), the parasite must acquire resources across the limiting membrane of its replicative niche, which is decorated with parasite proteins including those secreted from dense granules. We discovered a role for the host Endosomal Sorting Complex Required for Transport (ESCRT) machinery in host cytosolic protein uptake by T. gondii by disrupting host ESCRT function. We identified the transmembrane dense granule protein TgGRA14, which contains motifs homologous to the late domain motifs of HIV-1 Gag, as a candidate for the recruitment of the host ESCRT machinery to the PV membrane. Using an HIV-1 virus-like particle (VLP) release assay, we found that the motif-containing portion of TgGRA14 is sufficient to substitute for HIV-1 Gag late domain to mediate ESCRT-dependent VLP budding. We also show that TgGRA14 is proximal to and interacts with host ESCRT components and other dense granule proteins during infection. Furthermore, analysis of TgGRA14-deficient parasites revealed a marked reduction in ingestion of a host cytosolic protein compared to WT parasites. Thus, we propose a model in which T. gondii recruits the host ESCRT machinery to the PV where it can interact with TgGRA14 for the internalization of host cytosolic proteins across the PV membrane (PVM). These findings provide new insight into how T. gondii accesses contents of the host cytosol by exploiting a key pathway for vesicular budding and membrane scission.
Author summary Intracellular pathogens exploit their host to gain the resources necessary to sustain infection; however, precisely how the intracellular parasite Toxoplasma gondii acquires essential nutrients from its host remains poorly understood. Previous work showed that T. gondii is capable of internalizing host derived cytosolic proteins and delivering them to its lysosome-like compartment for degradation. However, the mechanism by which the material is trafficked across the membrane delimiting the replicative vacuole in which the parasite resides remained unclear. Here, we report a role for the parasite effector protein TgGRA14 in the recruitment of the host ESCRT machinery and in the uptake of host cytosolic proteins. Important human pathogens have developed strategies for exploiting the host ESCRT machinery for intracellular subsistence. Our study sheds lights on the strategy used by a eukaryotic pathogen in to exploit the host ESCRT machinery for the internalization of resources from its host cell.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje