RIG-I-like Receptors
About RIG-I-like Receptors
RIG-I-like receptors (RLRs) are a family of intracellular pattern recognition receptors (PRRs) that play a crucial role in the innate immune system's detection of viral infections. They are primarily involved in recognizing viral RNA molecules and initiating antiviral immune responses. The RLR family consists of three main members: retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated gene 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2). Here is an introduction to RIG-I-like receptors and their functions:
- RIG-I (Retinoic Acid-Inducible Gene I)
RIG-I is an intracellular protein predominantly expressed in immune cells, particularly in dendritic cells and macrophages. It consists of several domains, including two N-terminal caspase activation and recruitment domains (CARDs), a central DExD/H-box RNA helicase domain, and a C-terminal regulatory domain. RIG-I is mainly responsible for detecting short viral RNA molecules with a 5'-triphosphate (5'-ppp) moiety, characteristic of many RNA viruses.
- MDA5 (Melanoma Differentiation-Associated Gene 5)
MDA5 is another member of the RLR family that shares structural similarities with RIG-I. MDA5 is expressed in various cell types, including immune cells and epithelial cells. It recognizes long double-stranded RNA (dsRNA) molecules, typically produced during the replication of certain RNA viruses. Unlike RIG-I, MDA5 does not require a 5'- moiety for activation.
- LGP2 (Laboratory of Genetics and Physiology 2)
LGP2 is structurally similar to RIG-I and MDA5 but lacks the CARD domains that are critical for downstream signaling. As a result, LGP2 acts as a regulator of RIG-I and MDA5 signaling rather than directly initiating signaling cascades. LGP2 can bind viral RNA and modulate the activity of RIG-I and MDA5, influencing the overall antiviral immune response.
Fig. 1 Schematic illustration of the domains of RLRs. (Yangfu Jiang, et al., 2023)
a Both RIG-I and MDA5 have two N-terminal tandem caspase activation and recruitment domains (CARDs), two central Rec A domains (Hel-1 and Hel-2), and a C-terminal domain (CTD), while LGP2 is lack of CARD. b Under resting states, the CARDs of RIG-I are masked by an autoinhibitory conformation. The binding of 5′-ppp dsRNA to RIG-I triggers the unmasking of CARDs that allows signal transmission.
These receptors not only recognize RNA intermediates from viruses and bacteria, but also interact with endogenous RNA such as the mislocalized mitochondrial RNA, the aberrantly reactivated repetitive or transposable elements in the human genome. Evasion of RLRs-mediated immune response may lead to sustained infection, defective host immunity, and carcinogenesis. Therapeutic targeting RLRs may not only provoke anti-infection effects, but also induce anticancer immunity or sensitize “immune-cold” tumors to immune checkpoint blockade.
Functions of RIG-I-like Receptors
- Viral RNA Sensing: RLRs recognize viral RNA molecules in the cytoplasm of infected cells. RIG-I primarily detects short viral RNA with 5'-ppp, while MDA5 recognizes long dsRNA. Upon binding to viral RNA, RIG-I and MDA5 undergo conformational changes that expose their CARD domains, facilitating downstream signaling.
- Downstream Signaling: The exposed CARD domains of RIG-I and MDA5 interact with the mitochondrial antiviral signaling protein (MAVS), also known as IPS-1, VISA, or Cardif. This interaction leads to the activation of various signaling pathways, including the production of type I interferons (IFNs) and pro-inflammatory cytokines.
- Type I Interferon Response: Activation of RIG-I and MDA5 triggers the production of type I interferons, including interferon-alpha (IFN-α) and interferon-beta (IFN-β). Type I interferons play a crucial role in antiviral defense by inducing an antiviral state in neighboring cells, activating immune cells, and enhancing the overall immune response against viral infections.
- Amplification of Antiviral Responses: RLR activation also leads to the production of other pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). These cytokines contribute to the recruitment and activation of immune cells, inflammation, and the elimination of viral infections.
RLRs are essential for the detection of viral infections and the initiation of antiviral immune responses. Dysregulation or malfunction of RLRs can impair the host's ability to respond to viral infections, leading to increased susceptibility to viral diseases. Understanding the mechanisms of RLR signaling provides insights into antiviral defense strategies and the development of therapeutics aimed at enhancing immune responses against viral infections.
Fig. 2 RLR signaling and cellular regulation. (Ramos HJ, et al., 2011)
RIG-I and MDA5 signal through the IPS-1 signalsome located at mitochondria, mitochondrial membranes or peroxisomes. Signaling proceeds through multiple adaptors and leads to the bifurcation and activation of IRF-3 and NF-κB via the kinases TBK-1 and IKKɛ. Cellular factors known to contribute to regulation of multiple stages of RLR signaling are depicted in the figure. Factors involved in ubiquitin mediated regulation are denoted in red text, factors which require direct interaction with RLR signaling components are depicted in blue text and factors with unknown mechanisms of regulation are shown in black text.
Available Resources for RIG-I-like Receptors
Creative BioMart offers a wide range of quality tools related to RIG-I-like receptors, including recombinant proteins and more. At the same time, we provide personalized services according to the specific needs of our customers. In addition, we provide comprehensive resources, including involved pathways, protein functions, interacting proteins, related articles, and other relevant topics, to help advance research related to RIG-I-like receptors.
Fig. 3 Regulation of RLR-mediated signal transduction. A summary of the regulatory mechanisms of RLR/MAVS-mediated signaling by host and viral factors. (Onomoto K, et al., 2021)
a Activated RLRs interact with MAVS, localize to mitochondria, mitochondria-associated endoplasmic reticulum membranes (MAMs), and peroxisomes, where they activate downstream signaling. b RLRs accumulate in virus-induced stress granules (SGs) with viral RNAs, resulting in enhanced signaling. c Several host RNAs can be recognized by RLRs and are involved in the regulation of autoimmunity and cancer. Moreover, RLR/MAVS-mediated signaling is regulated by various host molecules: ubiquitin ligases/deubiquitinases (d), posttranslational modifiers (e), protein kinases/phosphatases (f), RNA-binding proteins (g), other host proteins (h), and autophagy regulators (i). These molecules are classified in square boxes (orange boxes: positive regulators; blue boxes: negative regulators). The molecules that inhibit or promote these regulatory molecules are shown on the right side of each column. Regulatory molecules of viral origin are shown in pink rounded rectangles.
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References:
- Jiang Y, Zhang H, Wang J, et al. Exploiting RIG-I-like receptor pathway for cancer immunotherapy[J]. Journal of Hematology & Oncology, 2023, 16(1).DOI:10.1186/s13045-023-01405-9.
- Ramos HJ, Gale M Jr. RIG-I like receptors and their signaling crosstalk in the regulation of antiviral immunity. Curr Opin Virol. 2011;1(3):167-176. doi:10.1016/j.coviro.2011.04.004
- Onomoto K, Onoguchi K, Yoneyama M. Regulation of RIG-I-like receptor-mediated signaling: interaction between host and viral factors. Cell Mol Immunol. 2021;18(3):539-555. doi:10.1038/s41423-020-00602-7
