Toxoplasma effector TgROP1 establishes membrane contact sites with the endoplasmic reticulum during infection
Chahat Mehra1, Jesús Alvarado Valverde2, Ana Margarida Nogueira Matias3,4
1Metabolism of Infection Group, Max Planck Institute for Biology of Ageing, Cologne, Germany.
Abstract:
Membrane contact sites (MCS) are essential for organelle communication in eukaryotic cells. Pathogens also establish MCS with host organelles, but the mechanisms underlying these interactions and their role in infection remain poorly understood. Here, using a fluorescence sensor and CRISPR-based loss-of-function screening, together with imaging and proteomics, we identify the parasite effector mediating MCS between host endoplasmic reticulum (ER) and the vacuole containing the intracellular parasite Toxoplasma gondii. TgROP1 acts as a tether and mimics a canonical FFAT motif to bind the host ER proteins VAPA and VAPB. The loss of VAPA/B abolished host ER-Toxoplasma MCS and decreased pathogen growth. These findings indicate that targeting of host MCS tethers is a strategy exploited by pathogens during infection, which could inform future treatment design.
Insights
Pathogens exploit membrane contact sites (MCS) for infection. Researchers found the parasite effector TgROP1 mimics host proteins to bind host ER, enabling pathogen-host organelle communication and aiding Toxoplasma gondii growth.
Area of Science:
- Cell Biology
- Infectious Diseases
- Parasitology
Background:
- Membrane contact sites (MCS) are crucial for organelle communication in eukaryotic cells.
- Pathogens can hijack MCS for their own benefit, but the mechanisms are poorly understood.
Purpose of the Study:
- To identify the parasite effector responsible for mediating MCS between the host endoplasmic reticulum (ER) and the vacuole containing Toxoplasma gondii.
- To understand the role of these MCS in pathogen infection and growth.
Main Methods:
- Utilized a fluorescence sensor and CRISPR-based loss-of-function screening.
- Employed advanced imaging and proteomics techniques.
Main Results:
- Identified the parasite effector TgROP1 as the mediator of MCS between host ER and the parasite vacuole.
- TgROP1 functions as a tether, mimicking a canonical FFAT motif to bind host ER proteins VAPA and VAPB.
- Disruption of VAPA/B proteins abolished host ER-Toxoplasma MCS and impaired parasite growth.
Conclusions:
- Pathogens strategically target host MCS tethers to facilitate infection.
- Understanding these interactions can inform the design of novel anti-parasitic therapies.
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