RIG-I pathway signaling of innate immunity against
RNA virus infection is organized between the ER and mitochondria on a subdomain of the ER called the mitochondrial-associated ER membrane (MAM). The RIG-I adaptor
protein MAVS transmits downstream signaling of
antiviral immunity, with signaling complexes assembling on the MAM in association with mitochondria and peroxisomes. To identify components that regulate MAVS signalosome assembly on the MAM, we characterized the
proteome of MAM, ER, and cytosol from cells infected with either
chronic (hepatitis C) or acute (Sendai)
RNA virus infections, as well as mock-infected cells. Comparative analysis of protein trafficking dynamics during both chronic and acute
viral infection reveals differential
protein profiles in the MAM during RIG-I pathway activation. We identified
proteins and biochemical pathways recruited into and out of the MAM in both chronic and acute
RNA viral infections, representing
proteins that drive immunity and/or regulate viral replication. In addition, by using this comparative proteomics approach, we identified 3 new MAVS-interacting
proteins, RAB1B, VTN, and LONP1, and defined LONP1 as a positive regulator of the RIG-I pathway. Our proteomic analysis also reveals a dynamic cross-talk between subcellular compartments during both acute and chronic
RNA virus infection, and demonstrates the importance of the MAM as a central platform that coordinates innate immune signaling to initiate immunity against
RNA virus infection.