Immune Netw.  2017 Apr;17(2):77-88. 10.4110/in.2017.17.2.77.

Mitochondrial Control of Innate Immunity and Inflammation

• Jin HS
• Suh HW
• Kim SJ
• Jo EK

• KMID: 2376865
• DOI: http://doi.org/10.4110/in.2017.17.2.77

Abstract

Mitochondria are key organelles involved in energy production, functioning as the metabolic hubs of cells. Recent findings emphasize the emerging role of the mitochondrion as a key intracellular signaling platform regulating innate immune and inflammatory responses. Several mitochondrial proteins and mitochondrial reactive oxygen species have emerged as central players orchestrating the innate immune responses to pathogens and damaging ligands. This review explores our current understanding of the roles played by mitochondria in regulation of innate immunity and inflammatory responses. Recent advances in our understanding of the relationship between autophagy, mitochondria, and inflammasome activation are also briefly discussed. A comprehensive understanding of mitochondrial role in toll-like receptor-mediated innate immune responses and NLRP3 inflammasome complex activation, will facilitate development of novel therapeutics to treat various infectious, inflammatory, and autoimmune disorders.

Keyword

Mitochondria; Inflammation; Innate immunity; Autophagy; Inflammasome

MeSH Terms

Autophagy
Immunity, Innate*
Inflammasomes
Inflammation*
Ligands
Mitochondria
Mitochondrial Proteins
Organelles
Reactive Oxygen Species
Inflammasomes
Ligands
Mitochondrial Proteins
Reactive Oxygen Species

Figure

• 

  Figure 1 Overview of RLRs signaling pathway. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) recognize the genomic RNA or RNA replication intermediates of viruses as cytoplasmic RNA sensors. Following viral infection, melanoma differentiation-associated protein 5 (MDA5) recognizes cytoplasmic viral long-scale double-stranded RNA (dsRNA) whereas RIG-I recognizes short viral dsRNA (non-self RNA). Upon recognition of viral dsRNA, MDA5 and RIG-I specifically ubiquitinated by TRIM65 and TRIM25 respectively initiate antiviral innate immune response via specific interaction with mitochondrial antiviral signaling protein (MAVS) by CARD-CARD interaction. MAVS modulates nuclear factor-kB (NF-kB) activity via IKK complex (IKK α/β/γ) activation. MAVS also interacts with TRAFs translocated onto mitochondria upon viral infection and subsequently induces recruitment of TBK1 and IκB kinase-ɛ (IKKɛ) to promote phosphorylation of interferon (IFN) regulatory factor 3 (IRF3) and IRF7. Phosphorylated IRF3 and IRF7 cause their homo-dimerization which is translocated to the nucleus. In the nucleus, homo-dimerized IRF3 and IRF7 bind to specific binding sites in the IFNβ and IFNα promoter respectively to stimulate type I IFN synthesis. Secreted type I IFNs (IFNβ and IFNα) binds to interferon alpha and beta receptor subunit 1 (IFNAR1) and subsequently induces phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT2, leading to the induction of nuclear translocation of IRF7/STAT1/STAT2 complex followed by promotion of IFN-stimulated genes (ISGs) transcription. Solid arrows indicate direct signaling. Dashed arrows indicate indirect signaling.

• 

  Figure 2 Positive and negative regulation of MAVS-mediated antiviral signaling pathway. Upon viral infection, sensing of viral dsRNA by RLRs induces the formation of MAVS signalosome on mitochondria followed by promotion in downstream IFN synthesis. TNF receptor-associated factor 6 (TRAF6), TNFR1–associated death domain protein (TRADD), tripartite motif 14 (TRIM14) and pyruvate carboxylase (PC) modulates canonical NF-κB signaling pathway. Activated IκB kinase (IKK) complex (IKK α/β/γ) induces phosphorylation of NF–κB inhibitor–α (IκBα), resulting in NF–κB nuclear translocation and transcriptional activation of proinflammatory cytokines gene expression. MAVS also interacts with TRAF2/3, TANK, IKKe and TBK1. TBK1-mediated phosphorylation of IRF3 and IRF7 and subsequent their dimerization promotes type I IFN gene expression through nuclear translocation. Various molecules are involved in negative regulation of MAVS signaling. Poly(RC)-binding protein (PCBP) 1 and PCBP2 induces Lys48-linked polyubiquitination of MAVS, resulting in its proteasomal proteosomal degradation. Also, Smad ubiquitin regulatory factor 2 (Smurf2) binding to MAVS reduces antiviral type I IFN production through proteosomal degradation of MAVS. 20S proteasomal subunit PSMA7 negatively regulates MAVS signaling by promoting degradation, NLR family member X1 (NLRX1) downregulates type I IFN production by inhibiting between MAVS and RIG-I direct interaction. Cytochrome c oxidase (CcO) complex subunit (COX5B) downregulates type I IFN production by physical interaction with MAVS. UBX-domain-containing protein UBXN1 inhibit MAVS oligomerization, resulting in inhibition of antiviral signaling pathway.

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