title: Reactive oxygen species induce virus-independent MAVS oligomerization in systemic lupus erythematosus.
abstract: The increased expression of genes induced by type I interferon (IFN) is characteristic of viral infections and systemic lupus erythematosus (SLE). We showed that mitochondrial antiviral signaling (MAVS) protein, which normally forms a complex with retinoic acid gene I (RIG-I)-like helicases during viral infection, was activated by oxidative stress independently of RIG-I helicases. We found that chemically generated oxidative stress stimulated the formation of MAVS oligomers, which led to mitochondrial hyperpolarization and decreased adenosine triphosphate production and spare respiratory capacity, responses that were not observed in similarly treated cells lacking MAVS. Peripheral blood lymphocytes of SLE patients also showed spontaneous MAVS oligomerization that correlated with the increased secretion of type I IFN and mitochondrial oxidative stress. Furthermore, inhibition of mitochondrial reactive oxygen species (ROS) by the mitochondria-targeted antioxidant MitoQ prevented MAVS oligomerization and type I IFN production. ROS-dependent MAVS oligomerization and type I IFN production were reduced in cells expressing the MAVS-C79F variant, which occurs in 30% of sub-Saharan Africans and is linked with reduced type I IFN secretion and milder disease in SLE patients. Patients expressing the MAVS-C79F variant also had reduced amounts of oligomerized MAVS in their plasma compared to healthy controls. Together, our findings suggest that oxidative stress-induced MAVS oligomerization in SLE patients may contribute to the type I IFN signature that is characteristic of this syndrome.
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA. akoenig@uvm.edu ibuskiew@uvm.edu.
authors.forename: Iwona A
authors.initials: IA
authors.lastname: Buskiewicz
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Montgomery
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Yasewicz
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Huber
authors.affiliation: MRC Mitochondrial Biology Unit, Wellcome Trust/MRC Building, Cambridge CB2 0XY, UK.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Murphy
authors.affiliation: WestCHEM School of Chemistry, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Hartley
authors.affiliation: Upstate University Hospital, State University of New York, Rheumatology Clinic, Syracuse, NY 13202, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Kelly
authors.affiliation: Hospital for Special Surgery, Weill Cornell Medical College, New York, NY 10021, USA.
authors.forename: Mary K
authors.initials: MK
authors.lastname: Crow
authors.affiliation: Upstate University Hospital, State University of New York, Rheumatology Clinic, Syracuse, NY 13202, USA.
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
authors.affiliation: Department of Medicine, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Ralph C
authors.initials: RC
authors.lastname: Budd
authors.affiliation: Department of Pathology, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA. akoenig@uvm.edu ibuskiew@uvm.edu.|Department of Medicine, Vermont Center for Immunology and Infectious Diseases, University of Vermont, Burlington, VT 05405, USA.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koenig
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D019943:Amino Acid Substitution; D000818:Animals; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism*; D008214:Lymphocytes / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D055503:Protein Multimerization; D017382:Reactive Oxygen Species / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D017382:Reactive Oxygen Species; C512612:MAVS protein, mouse; C505371:MAVS protein, human