TLR Steps

Question 1

Endosome cascade

Answer 1

When triggered by these TLRs, the MyD88-
associated IRAK1 directly phosphorylates IRF7. This allows IRF7 dimerization, activation, nuclear
translocation, and induction of IFN gene expression.

As mentioned above, after the endosomal TLR3 dimer binds viral double-stranded RNA, it
associates with the TRIF adaptor instead of MyD88.

TRIF binds and activates TRAF3 which generates a scaffold that recruits a kinase complex containing adaptors NEMO and TANK
(TRAF family member–associated NF-kB activator) and protein kinases IKKε and TBK1 (TANK-binding kinase 1).

TBK1 phosphorylates and activates IRF3 and IRF7, each of which dimerizes and enters the nucleus, inducing the transcription of the IFN-α and IFN-β genes.

As a somewhat later response, TRIF also can activate TRAF6, initiating signaling events that lead to some NF-κB
activation and inflammatory cytokine production.

Question 2

What is the myD88 pathway?

Answer 2

MyD88 recruits IRAK1 (IL-1 receptor–associated kinase 1) and IRAK4.

IRAK1 phosphorylates itself and TRAF6 (tumor necrosis factor receptor–associated factor 6), activating it.

TRAF6 creates a scaffold that serves as an organizing center for subsequent signaling components.

The adapter proteins TAB1 and TAB2 (TAK1-binding proteins 1 and 2) bring associated TAK1 (transforming
growth factor-β-activated kinase 1) into proximity with IRAK1, which phosphorylates and activates
TAK1.

The IKK (inhibitor of κB kinase) complex, consisting of NEMO (NF-κB essential modifier),
IKKα, and IKKβ, is then recruited, enabling TAK1 to phosphorylate and activate IKKβ.

This leads to the final steps resulting in the activation of NF-κB.

Inactive NF-κB is retained in the cytoplasm byits IκB (inhibitor of NF-κB) subunit. Activated IKK phosphorylates IkB, leading to its degradation and the release of NF-κB, allowing it to enter the nucleus and activate gene expression.

TAK1 does double duty in this TLR signaling cascade. After separating from the IKK complex, it
activates MAPK signaling pathways that result in the activation of transcription factors including
Fos and Jun, which make up the AP-1 dimer.

Both NF-κB and AP-1 are essential for activating key
antimicrobial proteins and peptides as well as proinflammatory cytokines and chemokines that are
of key importance in the innate immune response.