title: Mitochondrially localised MUL1 is a novel modulator of antiviral signaling.
abstract: The innate immune response to virus must be balanced to eliminate infection yet limit damaging inflammation. A critical arm of the antiviral response is launched by the retinoic acid-inducible-gene I (RIG-I) protein. RIG-I is activated by viral RNA then associates with the mitochondrial antiviral signaling (MAVS) protein to subsequently induce potent inflammatory cytokines. Here, we demonstrate the mitochondrial E3 ubiquitin protein ligase 1 (MUL1) is a crucial moderator of RIG-I signaling. MUL1 is localized to the mitochondria where it interacts with MAVS and catalyzes RIG-I post-translational modifications that inhibit RIG-I-dependent cell signaling. Accordingly, depletion of MUL1 potentiated RIG-I mediated nuclear factor-kappa B (NF-κB) and interferon (IFN) β reporter activity. Moreover, depletion of MUL1 boosted the antiviral response and increased proinflammatory cytokines following challenge with the RNA mimetic poly I:C and Sendai virus. We therefore submit that MUL1 is a novel regulator of the RIG-I-like receptor-dependent antiviral response, that otherwise functions to limit inflammation.
authors: Centre for Innate Immunity and Infectious Diseases, Monash Institute of Medical Research, Monash University, Melbourne, Victoria, Australia.
authors: Kristie
authors: K
authors: Jenkins
authors: Jing Jing
authors: JJ
authors: Khoo
authors: Anthony
authors: A
authors: Sadler
authors: Rebecca
authors: R
authors: Piganis
authors: Die
authors: D
authors: Wang
authors: Natalie A
authors: NA
authors: Borg
authors: Kathryn
authors: K
authors: Hjerrild
authors: Jodee
authors: J
authors: Gould
authors: Belinda J
authors: BJ
authors: Thomas
authors: Phillip
authors: P
authors: Nagley
authors: Paul J
authors: PJ
authors: Hertzog
authors: Ashley
authors: A
authors: Mansell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism*; D018946:Chemokine CCL5 / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D011971:Receptors, Immunologic; D025842:SUMO-1 Protein / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D018946:Chemokine CCL5; D016207:Cytokines; C505371:MAVS protein, human; D011971:Receptors, Immunologic; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D025821:Polyubiquitin; C529067:MUL1 protein, human; D044767:Ubiquitin-Protein Ligases; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases