RIG-I
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1. 본문
RIG-I (Retinoic acid-inducible gene I) is a crucial component of the innate immune system, acting as a cytosolic pattern recognition receptor (PRR). It plays a key role in detecting viral infections and triggering an antiviral response. Here's a breakdown of RIG-I:
Function:
- Viral RNA Sensor: RIG-I primarily senses viral RNA in the cytoplasm of cells. It specifically recognizes:
- Short double-stranded RNA (dsRNA).
- Single-stranded RNA (ssRNA) with a 5'-triphosphate end, a characteristic often found in viral RNA but not in host RNA.
- Initiates Antiviral Response: Upon binding to viral RNA, RIG-I undergoes conformational changes and activates a signaling cascade.
- Type I Interferon Production: This cascade leads to the production of type I interferons (IFNs), primarily IFN-α and IFN-β. Type I IFNs are critical for:
- Limiting viral spread to neighboring cells.
- Promoting an innate immune response, including inflammation.
- Activating the adaptive immune system.
- Pro-inflammatory Cytokine Production: Besides IFNs, RIG-I activation also stimulates the production of pro-inflammatory cytokines, further enhancing the immune response.
- Detects various viruses including, West Nile virus, Japanese Encephalitis virus, influenza A, Sendai virus, flavivirus, and coronaviruses
Structure:
- Encoded by: The *DDX58* gene in humans.
- Domains:
- CARDs (Caspase Activation and Recruitment Domains): Two N-terminal CARDs are essential for interacting with the adaptor protein MAVS (mitochondrial antiviral signaling protein), also known as VISA, Cardif, or IPS-1.
- Helicase Domain: A central ATP-dependent DExD/H box RNA helicase domain is responsible for binding to RNA and unwinding it.
- CTD (C-terminal Domain) and RD (Repressor Domain): The C-terminal domain (CTD) binds to viral RNA, while the repressor domain (RD) regulates RIG-I activity.
Mechanism of Activation:1. Recognition: In the resting state, RIG-I is auto-inhibited. Upon viral infection, the CTD of RIG-I binds to viral RNA (short dsRNA or 5'-triphosphate ssRNA).
2. Conformational Change: RNA binding leads to a conformational change, exposing the CARD domains.
3. Oligomerization: RIG-I forms a complex with the viral RNA and then undergoes homooligomerization, forming filaments.
4. MAVS Interaction: The exposed CARD domains of RIG-I interact with the CARD domains of MAVS, which is located on the mitochondria.
5. Signal Transduction: MAVS acts as an adaptor protein, recruiting downstream signaling molecules like TBK1 (TANK-binding kinase 1) and IKK (IκB kinase).
6. Transcription Factor Activation: These kinases phosphorylate and activate transcription factors, including IRF3 (interferon regulatory factor 3), IRF7, and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells).
7. Interferon and Cytokine Production: The activated transcription factors move to the nucleus and induce the expression of type I interferons (IFN-α and IFN-β) and other pro-inflammatory cytokines.
Regulation:
- RIG-I expression can be induced by various factors, including retinoic acid, lipopolysaccharide (LPS), IFN, and viral infection itself.
- It has been found that RIG-I activation can also cause damage to organs and tissues.
- Self-RNAs do not activate RIG-I signaling because their 5'ppp is capped by 2'O-methylation.
Other Roles:Besides its antiviral functions, there's evidence that RIG-I may also be involved in:
- Granulocyte production and differentiation.
- Bacterial phagocytosis.
- Regulation of cell migration.
- Responding to cytosolic DNA.
- Inflammation related to non-viral triggers like LPS and certain cytokines.
- Plays a role in macrophage activation.
RIG-I is part of a family of receptors called RIG-I-like receptors (RLRs), which also includes MDA5 (Melanoma Differentiation-Associated protein 5) and LGP2 (Laboratory of genetics physiology 2).
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