Mitochondrial-associated endoplasmic reticulum membranes (MAM) form innate immune synapses and are targeted by hepatitis C virus.

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.

• Authors: Stacy M Horner, Helene Minyi Liu, Hae Soo Park, Jessica Briley, Michael Gale Jr
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 108 Issue 35 Pg. 14590-5 (Aug 30 2011) ISSN: 1091-6490 [Electronic] United States
• PMID: 21844353 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• MAVS protein, human
• NS3 protein, hepatitis C virus
• NS4B protein, flavivirus
• Receptors, Immunologic
• Viral Nonstructural Proteins
• RIGI protein, human
• DEAD Box Protein 58
• DEAD-box RNA Helicases

Topics

• Adaptor Proteins, Signal Transducing (physiology)
• DEAD Box Protein 58
• DEAD-box RNA Helicases (physiology)
• Endoplasmic Reticulum (physiology)
• Hepacivirus (immunology)
• Humans
• Immunity, Innate
• Immunological Synapses (physiology)
• Intracellular Membranes (physiology)
• Mitochondria (physiology)
• Receptors, Immunologic
• Viral Nonstructural Proteins (analysis, physiology)