General signal transduction principle
Immune cell activation requires the switching on of specific genes. The signal for this originates at the membrane when a pattern recognition receptor binds to a microbial molecule (PAMP).
The extracellular domain of a TLR changes its conformation, and this conformational change is transmitted to the internal TIR domain. From there, a signaling chain composed of two types of molecules extends deep into the cytoplasm:
- Adaptor proteins (MyD88, TRIF, TIRAP, TRAM) act as molecular "adapters", linking components of the chain together.
- Kinases are enzymes that phosphorylate target proteins, driving them into an active state.
The ultimate goal of this relay is nuclear transcription factors. They bind to DNA and initiate cytokine synthesis. In a resting cell, these factors are either absent or securely blocked by inhibitors.
Classical pathway and the NF-κB factor
Almost all receptors (except TLR-3) utilize a pathway based on the MyD88 adaptor. It acts as a bridge between the receptor and the IRAK-4 enzyme. The signal then cascades through IRAK-1, the ubiquitin ligase TRAF6, and the kinase TAK1.
Following this, a crucial enzyme—the tyrosine phosphatase IKK—is activated.
- In the cytoplasm of a resting cell, the main inflammation factor NF-κB is tightly bound to the inhibitor protein IκB.
- The IKK complex phosphorylates this inhibitor.
- Ubiquitin tags are attached to the phosphorylated IκB, targeting it for destruction in the proteasome.
- The liberated NF-κB dimer translocates to the nucleus and "switches on" robust transcription of pro-inflammatory molecules.
Cascade branching: MAP kinases and interferons
The signal can branch into alternative routes, shaping a flexible cellular response.
MAP cascade: At the level of the TAK1 kinase, the pathway can branch, triggering first-tier serine/threonine MAP kinases (JNK, p38). This leads to the assembly of the AP-1 factor, which is essential both for immediate inflammation and subsequent adaptive immunity.
MyD88-independent pathway: Characteristic of TLR-3 and TLR-4. It lacks the MyD88 protein, and its role is fulfilled by the TRIF adaptor. It can activate NF-κB via the RIP1 enzyme or trigger a branch involving TRAF3. The second branch activates the IRF3 transcription factor, inducing the cell to synthesize interferon-beta (IFNβ).
Endolysosomal receptors: TLRs 7, 8, and 9 reside inside endolysosomes, detecting intracellular parasites and viruses. They operate via MyD88 but form a complex perireceptor assembly that additionally activates the IRF7 factor. The latter translocates to the nucleus, where it switches on interferon-alpha (IFNα) genes.
Tolerance and cytosolic NLR receptors
Immunity must halt inflammation in a timely manner. When a membrane TLR binds its ligand, it eventually internalizes (sinks into the cell) and loses contact with the MyD88 protein. This induces tolerance—the cell temporarily (for 2–3 days) ceases to respond to the same pathogen.
If a pathogen breaches the cytosol, it is intercepted by other receptors—the NLR family (e.g., NOD1/2). They recognize bacterial muramyl peptides and utilize the RICK enzyme to activate IKK and MAP kinases. The fundamental difference between NLRs and certain TLRs is that they do not trigger the activation of interferon genes.
Briefly: answers to topical questions
What specific PAMPs are recognized by TLR-2, TLR-3, TLR-4, and TLR-9 receptors?
TLR-2, TLR-3, TLR-4, and TLR-9 receptors specifically recognize various lipid-containing structures, carbohydrates, and pathogen nucleic acids.
- TLR-2—in a complex with TLR-1, recognizes triacylated lipopeptides, peptidoglycan, teichoic and lipoteichoic acids, zymosan, lipoarabinomannan, and porin; paired with TLR-6, it recognizes diacylated lipopeptides.
- TLR-3—recognizes viral double-stranded RNA (dsRNA).
- TLR-4—recognizes lipopolysaccharide (LPS) of gram-negative bacteria (in complex with MD2) and heat shock protein HSP60.
- TLR-9—recognizes DNA fragments enriched with unmethylated CpG motifs of bacteria and viruses.
Which receptors belong to the NLR family and what signaling pathways do they activate?
The NLR family of cytoplasmic pattern recognition receptors includes NOD1, NOD2, NALP1, NALP3, and IPAF.
- NOD1 and NOD2 activate the RICK factor, leading to the activation of the IKK complex with subsequent formation of the NF-κB transcription factor, and also trigger the MAP kinase cascade resulting in AP-1 formation. Interferon gene activation does not occur in this process.
- NALP1, NALP3, and IPAF participate in inflammasome assembly, inside which caspase-1 is activated, which is necessary for the processing of pro-inflammatory cytokines.
"TRI goes via TRIF": the TLR-3 receptor is the only one in the entire family that completely avoids the MyD88-dependent pathway, transducing signals exclusively via the TRIF adaptor.
Class and exam questions
Why is the TLR-4 receptor considered unique?
It is capable of utilizing both main signaling cascades. Initially, it acts as a MyD88-dependent receptor at the membrane, and after internalization, as a MyD88-independent receptor (via TRIF and TRAM) within an endosome.
What is the main objective of NF-κB and AP-1 activation?
Their primary task is to reprogram the cell into an effector state: triggering the synthesis of cytokines, costimulatory molecules, bactericidal factors, and adhesion molecules necessary for the development of inflammation.
How do membrane and endolysosomal TLRs functionally differ?
Membrane receptors recognize extracellular microbes and stimulate classical inflammation. Endolysosomal receptors respond to intracellular agents (viruses) and additionally switch on the synthesis of interferons (IRF7) for antiviral defense.
What else to study on this topic
- Structure and functions of the intracellular TIR domain
- The role of MAP kinases and the AP-1 transcription factor
- Activation of IRF3 and IRF7 factors and interferon synthesis
- Mechanisms of IκB inhibitor degradation in the proteasome
- Signal transduction from cytosolic receptors of the NLR family
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