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Mitochondria-associated ER Membranes (MAMs) and Glycosphingolipid Enriched Microdomains (GEMs): Isolation from Mouse Brain
Published on: March 4, 2013
Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by
Stacy M Horner1, Helene Minyi Liu, Hae Soo Park
1Department of Immunology, University of Washington School of Medicine, Seattle, WA 98195, USA.
Abstract:
RIG-I is a cytosolic pathogen recognition receptor that engages viral RNA in infected cells to trigger innate immune defenses through its adaptor protein MAVS. MAVS resides on mitochondria and peroxisomes, but how its signaling is coordinated among these organelles has not been defined. Here we show that a major site of MAVS signaling is the mitochondrial-associated membrane (MAM), a distinct membrane compartment that links the endoplasmic reticulum to mitochondria. During RNA virus infection, RIG-I is recruited to the MAM to bind MAVS. Dynamic MAM tethering to mitochondria and peroxisomes then coordinates MAVS localization to form a signaling synapse between membranes. Importantly, the hepatitis C virus NS3/4A protease, which cleaves MAVS to support persistent infection, targets this synapse for MAVS proteolysis from the MAM, but not from mitochondria, to ablate RIG-I signaling of immune defenses. Thus, the MAM mediates an intracellular immune synapse that directs antiviral innate immunity.
Insights
The mitochondrial-associated membrane (MAM) acts as an immune synapse, coordinating RIG-I and MAVS signaling during viral RNA infection to activate innate immunity.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- RIG-I is a cytosolic receptor sensing viral RNA to initiate innate immune responses.
- MAVS, an adaptor protein, localizes to mitochondria and peroxisomes, but its signaling coordination is unclear.
Purpose of the Study:
- To investigate the role of MAVS localization and signaling coordination in innate immunity.
- To identify the specific organelle sites involved in MAVS-mediated antiviral signaling.
Main Methods:
- Utilized cell-based assays to track RIG-I and MAVS localization during RNA virus infection.
- Investigated the role of the mitochondrial-associated membrane (MAM) in MAVS signaling.
- Examined the impact of hepatitis C virus NS3/4A protease on MAVS signaling at the MAM.
Main Results:
- The MAM serves as a critical platform for RIG-I and MAVS interaction during viral infection.
- MAVS forms a signaling synapse at the MAM, integrating signals from mitochondria and peroxisomes.
- Hepatitis C virus protease specifically targets MAVS at the MAM to disrupt innate immune signaling.
Conclusions:
- The MAM functions as an intracellular immune synapse, crucial for orchestrating antiviral innate immunity.
- Targeting the MAM-mediated immune synapse is a strategy employed by viruses to evade host defenses.
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