MDA5

Abstract: Mitochondria are known to be semi‐autonomous organelles that are responsible for energy production and cellular respiration. Mitochondria break down glucose to release energy in the form of ATP through oxidative phosphorylation. However, as a by‐product, a steady stream of reactive oxygen species (ROS) is released from these cellular powerhouses. ROS can potentially cause damage to cellular components, and are therefore closely linked to diseases such as Alzheimer disease and cancer. Recently, mitochondria were also found to have a crucial role in innate immunity. Innate immune responses against invading viruses rely on the detection of viral pathogen‐associated molecular patterns (PAMPs) and the subsequent production of antiviral cytokines such as type I interferons (IFNs). One prototypical viral PAMP is double‐stranded (ds)RNA, which can be detected by Toll‐like receptor 3 (TLR3) in endosomes (Akira & Takeda, 2004). TLR3 was the first reported dsRNA receptor able to signal to interferon regulatory factor (IRF) and NF‐κB, which are essential transcription factors that regulate type I IFN production (Fig 1). Since then, two homologous RNA helicases—retinoic‐acid‐inducible gene I (RIG‐I) and melanoma‐differentiation‐associated protein 5 (MDA5)—have been identified as cytoplasmic sensors of viral‐derived RNA (Yoneyama et al , 2004). Figure 1. Mitochondria as anti‐pathogen platforms. Through its mitochondrial anchor (MA) sequence, Cardif is targeted to the outer membrane of mitochondria, where it orchestrates RLH‐dependent antiviral responses through the recruitment of both viral RNA sensors (RIG‐I or MDA5) and effector proteins (IKK). Several cellular (SIKE, PIN1) but also viral (for example, the protease of HCV) proteins tightly regulate the antiviral response. NLRX1, another mitochondria‐targeted protein (MT), might act as a negative regulator of Cardif signalling, diminishing virally induced Cardif–RLH interactions. However, NLRX1 also promotes ROS production at the mitochondria, which consequently helps to fight bacteria and viruses. How NLRX1 performs these functions, and how it becomes activated, remain unanswered questions. CARD, …

Abstract: Abstract Retinoic acid-inducible gene I (RIG-I) is the most front-line cytoplasmic viral RNA sensor and induces antiviral immune responses. RIG-I recognizes short double-stranded (dsRNA) (< 500 bp), but not long dsRNA (> 500 bp) to trigger antiviral signaling. Since RIG-I is capable of binding with dsRNA irrespective of size, length-dependent RIG-I signaling remains elusive. Here, we demonstrated that RIG-I bound to long dsRNA with slow kinetics. Remarkably, RIG-I/short dsRNA complex efficiently dissociated in an ATP hydrolysis-dependent manner, whereas RIG-I/long dsRNA was stable and did not dissociate. Our study suggests that the dissociation of RIG-I from RIG-I/dsRNA complex could be a step for efficient antiviral signaling. Dissociated RIG-I exhibited homo-oligomerization, acquiring ability to physically associate with MAVS, and biological activity upon introduction into living cells. We herein discuss common and unique mechanisms of viral dsRNA recognition by RIG-I and MDA5.