Overview of Signaling Pathways Downstream of RLR Detection of Virus Infection

1. Activation of RLRs: RIG-I-like receptors (RLRs), including RIG-I (Retinoic acid-inducible gene I) and MDA5 (Melanoma differentiation-associated protein 5), recognize viral RNA in the cytoplasm of infected cells. Upon binding to viral RNA, RLRs undergo a conformational change, exposing their caspase activation and recruitment domains (CARDs), which are essential for downstream signaling.
2. Interaction with MAVS: The activated RLRs interact with MAVS (mitochondrial antiviral signaling protein) through homotypic CARD-CARD interactions. MAVS serves as a critical adaptor protein localized on the outer mitochondrial membrane, facilitating the transmission of signals from RLRs to downstream effector molecules.
3. Activation of TRAFs: MAVS activation leads to the recruitment and activation of TRAFs, particularly TRAF3 and TRAF6. TRAF3 plays a crucial role in the activation of IRF3, while TRAF6 is involved in the activation of NF-κB and MAPK signaling pathways.
4. Activation of IRF3: MAVS-mediated activation of TRAF3 leads to the phosphorylation and subsequent activation of IRF3 (Interferon Regulatory Factor 3). Activated IRF3 forms homodimers or heterodimers with other transcription factors and translocates to the nucleus, where it binds to the promoter regions of type I interferon genes, such as IFN-β, inducing their transcription.
5. Activation of NF-κB: TRAF6, which is recruited to MAVS upon its activation, activates the NF-κB (Nuclear Factor-kappa B) signaling pathway. TRAF6 mediates the activation of the IκB kinase (IKK) complex, leading to the phosphorylation and subsequent degradation of inhibitory IκB proteins. This results in the release and nuclear translocation of NF-κB dimers, such as p50/p65, which regulate the transcription of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β.
6. Activation of AP-1: MAVS signaling can also activate the Mitogen-Activated Protein Kinase (MAPK) pathway, leading to the activation of transcription factors such as AP-1 (Activator Protein-1). MAPKs, including ERK, JNK, and p38, are activated downstream of TRAFs or through direct interactions with MAVS. Activated AP-1 regulates the expression of genes involved in inflammation, cell proliferation, and apoptosis, contributing to the antiviral response.

Overall, the signaling cascade from RLRs to MAVS to TRAFs to transcription factors IRF3, NF-κB, and AP-1 orchestrates a coordinated immune response against viral infections, leading to the induction of type I interferons, pro-inflammatory cytokines, and other antiviral effectors that help control viral replication and spread.

Next Topic: The Interferon Beta “Enhanceosome”

Source: ChatGPT response prompted and edited by Joel Graff.

• Immunology (Table of Contents for Entire Course – FREE!)
  • Other content for Unit 2: The Innate Immune System