RESUMO
Mitochondria are multi-functioning organelles that participate in a wide range of biologic processes from energy metabolism to cellular suicide. Mitochondria are also involved in the cellular innate immune response against microorganisms or environmental irritants, particularly in mammals. Mitochondrial-mediated innate immunity is achieved by the activation of two discrete signaling pathways, the NLR family pyrin domain-containing 3 inflammasomes and the retinoic acid-inducible gene I-like receptor pathway. In both pathways, a mitochondrial outer membrane adaptor protein, called mitochondrial antiviral signaling MAVS, and mitochondria-derived components play a key role in signal transduction. In this review, we discuss current insights regarding the fundamental phenomena of mitochondrial-related innate immune responses, and review the specific roles of various mitochondrial subcompartments in fine-tuning innate immune signaling events. We propose that specific targeting of mitochondrial functions is a potential therapeutic approach for the management of infectious diseases and autoinflammatory disorders with an excessive immune response.
Assuntos
Interações Hospedeiro-Patógeno/imunologia , Imunidade Inata , Mitocôndrias/imunologia , Infecções por Vírus de RNA/imunologia , Vírus de RNA/imunologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Animais , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Humanos , Inflamassomos , MicroRNAs/genética , MicroRNAs/imunologia , Mitocôndrias/genética , Mitocôndrias/virologia , Membranas Mitocondriais/imunologia , Membranas Mitocondriais/virologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Infecções por Vírus de RNA/genética , Infecções por Vírus de RNA/patologia , Infecções por Vírus de RNA/virologia , Vírus de RNA/genética , Vírus de RNA/patogenicidade , Receptores Imunológicos/genética , Receptores Imunológicos/imunologia , Transdução de SinaisRESUMO
Mitochondria, dynamic organelles that undergo cycles of fusion and fission, are the powerhouses of eukaryotic cells and are also involved in cellular innate antiviral immunity in mammals. Mitochondrial antiviral immunity depends on activation of the cytoplasmic retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathway and the participation of a mitochondrial outer membrane adaptor protein called MAVS (mitochondrial antiviral signaling). We found that cells that lack the ability to undergo mitochondrial fusion as a result of targeted deletion of both mitofusin 1 (Mfn1) and mitofusin 2 (Mfn2) exhibited impaired induction of interferons and proinflammatory cytokines in response to viral infection, resulting in increased viral replication. In contrast, cells with null mutations in either Mfn1 or Mfn2 retained their RLR-induced antiviral responses. We also found that a reduced mitochondrial membrane potential (ΔΨ(m)) correlated with the reduced antiviral response. The dissipation in ΔΨ(m) did not affect the activation of the transcription factor interferon regulatory factor 3 downstream of MAVS, which suggests that ΔΨ(m) and MAVS are coupled at the same stage in the RLR signaling pathway. Our results provide evidence that the physiological function of mitochondria plays a key role in innate antiviral immunity.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Fibroblastos/metabolismo , Potencial da Membrana Mitocondrial/fisiologia , Transdução de Sinais , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Western Blotting , Carbonil Cianeto m-Clorofenil Hidrazona/farmacologia , Células Cultivadas , Embrião de Mamíferos/citologia , Vírus da Encefalomiocardite/fisiologia , Fibroblastos/citologia , Fibroblastos/virologia , GTP Fosfo-Hidrolases/genética , GTP Fosfo-Hidrolases/metabolismo , Expressão Gênica , Células HEK293 , Interações Hospedeiro-Patógeno , Humanos , Interferon beta/genética , Interleucina-6/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Camundongos Knockout , Microscopia de Fluorescência , RNA Helicases/genética , RNA Helicases/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Vírus Sendai/fisiologia , Desacopladores/farmacologiaRESUMO
The innate immune response to viral infection involves the activation of multiple signaling steps that culminate in the production of type I interferons (IFNs). Mitochondrial antiviral signaling (MAVS), a mitochondrial outer membrane adaptor protein, plays an important role in this process. Here, we report that mitofusin 2 (Mfn2), a mediator of mitochondrial fusion, interacts with MAVS to modulate antiviral immunity. Overexpression of Mfn2 resulted in the inhibition of retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA-5), two cytosolic sensors of viral RNA, as well as of MAVS-mediated activation of the transcription factors interferon regulatory factor 3 (IRF-3) and nuclear factor kappaB (NF-kappaB). In contrast, loss of endogenous Mfn2 enhanced virus-induced production of IFN-beta and thereby decreased viral replication. Structure-function analysis revealed that Mfn2 interacted with the carboxyl-terminal region of MAVS through a heptad repeat region, providing a structural perspective on the regulation of the mitochondrial antiviral response. Our results suggest that Mfn2 acts as an inhibitor of antiviral signaling, a function that may be distinct from its role in mitochondrial dynamics.