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Mitochondrial RNA, a new trigger of the innate immune system

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Abstract Mitochondria play a pivotal role in numerous cellular processes. One of them is regulation of the innate immune pathway. In this instance, mitochondria function in two different aspects of regulatory mechanisms. First, mitochondria are part of the antiviral signaling cascade that is triggered in the cytoplasm and transmitted to effector proteins through mitochondria‐localized proteins. Second, mitochondria can become an endogenous source of innate immune stimuli. Under some pathophysiological conditions, mitochondria release to the cytoplasm immunogenic factors, such as mitochondrial nucleic acids. Here, we focus on immunogenic mitochondrial double‐stranded RNA (mt‐dsRNA) and its origin and metabolism. We discuss factors that are responsible for regulating mt‐dsRNA and its escape from mitochondria, emphasizing the contribution of polynucleotide phosphorylase (PNPase, PNPT1). Finally, we review current knowledge of the role of PNPase in human health and disease. This article is categorized under: RNA in Disease and Development > RNA in Disease
Activation of the innate immune response by foreign RNA. Key steps of the process are presented on the simplified diagram. Solid line arrows represent changes regarding given protein(s), whereas dashed line arrows depict effects on other protein(s) or processes. Briefly, the cytosolic receptors MDA5 and RIG‐I recognize and bind foreign RNA, such as viral RNA. Upon RNA binding MDA5 and RIG‐I activate and, with the assistance of other factors (not shown), undergo homo‐oligomerization. In turn, MDA5 and/or RIG‐I oligomers interact with the mitochondrial‐localized MAVS protein and lead to its aggregation. MAVS aggregates attract subsequent factors, including TRAF proteins (TRAF2, TRAF3, TRAF5, and TRAF6), which promote further steps of the pathway. These encompass phosphorylation of IRF3, IRF7, and NF‐κB transcription factors by TBK1, IKKε, and IKKα/β/γ kinases, respectively. The phosphorylation reactions lead to activation of the transcription factors; in the case of NF‐κB, by dissociation of the phosphorylated component of the complex, IκBα. The activated IRF3, IRF7, and NF‐κB translocate to the nucleus, where they bind to specific DNA sequences and upregulate expression of genes encoding type I IFNs and proinflammatory cytokines
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Activation of the innate immune response by mt‐dsRNA. Under normal conditions, the SUV3‐PNPase complex keeps mt‐dsRNAs at low level by removing antisense mtRNA or degrading mt‐dsRNA in the mitochondrial matrix. Under severe stress conditions, mt‐dsRNA accumulates and is released into the cytoplasm depending on the BAK/BAX pores, where it is bound by dsRNA sensors. Activation of MDA5 results in the stimulation of the type I IFN response, activation of PKR leads to an inhibition of global translation and/or to apoptosis. A mechanism of the function of IMS‐localized PNPase has not been revealed
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Basic steps of biogenesis and metabolism of RNAs in human mitochondria. Map of the human mitochondrial genome (not to scale) and schematic view of basics steps of RNA life‐cycle are shown. mtDNA transcription is initiated from two promoters (ITL and ITH), one for each strand and performed by POLRMT in cooperation with others factors. The processing of nascent polycistronic transcripts into individual molecules is performed by the RNase P and RNase Z. Once mRNAs, rRNAs, or tRNAs are released, immature transcripts are stabilized, maturated, or modified in different ways depending on their nature. Vast amount of non‐coding RNA is produced. The major players in mitochondrial RNA surveillance and decay are PNPase and SUV3 that form the degradosome complex. The complex is supported by GRSF1, which binds to G‐quadruplexes structures and melts them. This enhances RNA degradation by the degradosome to oligonucleotides. These short RNA degradation intermediates are next processed by REXO2
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