Nfkb signalling pathway · HTM
NF-κB is the master switch of inflammation and immune survival. Almost every innate and adaptive receptor funnels into it. In the canonical arm, TNF engaging TNFR1/TNFR2 builds a TRADD–RIPK1–TRAF2–cIAP1/2 complex that is decorated with M1 chains by LUBAC (HOIP); LPS sensed by TLR4–CD14–MD-2 and IL-1β sensed by IL-1R recruit MyD88/TRIF and the IRAK4–IRAK1–TRAF6 module; antigen through CD3/CD28 drives PKCθ and the CARMA1–BCL10–MALT1 signalosome. All three converge on TAK1/TAB2, which activates the IKKα–IKKβ–NEMO complex; IKKβ phosphorylates IκBα for proteasomal destruction, freeing p65 (RelA)/p50 to enter the nucleus and transcribe TNF, IL-6, IL-1β, CXCL1, CCL2, iNOS, COX-2, Bcl-2, Bcl-xL, XIAP, ICAM-1 and VCAM-1. In the non-canonical arm, CD40, OX40, 4-1BB, LTβR, BAFF-R and RANK trigger loss of TRAF3, stabilising NIK, which drives IKKα homodimers to process p100 into p52 for p52/RelB-dependent CCL19/CCL21 lymphoid organogenesis. The deubiquitinases A20 and CYLD and the IκBα feedback loop terminate the response. Click any protein for the matching Assay Genie In Vivo antibody or ELISA kit.
Canonical arm — three inputs, one IKK complex. TNF binding TNFR1 recruits TRADD and RIPK1, which are ubiquitinated by TRAF2 with cIAP1/cIAP2 (K63 chains) and by LUBAC, whose catalytic subunit HOIP (RNF31) adds linear M1 chains; TNFR2 signals through TRAF2 without a death domain. In parallel, LPS is delivered by CD14 and MD-2 to TLR4, and IL-1β engages IL-1R; both recruit MyD88 (TLR4 also uses TRIF), assembling the Myddosome with IRAK4 and IRAK1 and activating the E3 ligase TRAF6. Antigen receptor signalling adds a third input: CD3 plus CD28 co-stimulation activates PKCθ, which nucleates the CARMA1–BCL10–MALT1 (CBM) signalosome, MALT1 acting both as a scaffold and as a paracaspase. Every one of these ubiquitin platforms recruits TAK1 with TAB2.
IKK, IκBα and nuclear p65/p50. TAK1 phosphorylates the activation loop of IKKβ within the IKKα–IKKβ–NEMO (IKKγ) holocomplex — NEMO’s ubiquitin-binding domain is what tethers IKK to the M1/K63 chains built above. Activated IKKβ phosphorylates IκBα on S32/S36, marking it for β-TrCP-dependent proteasomal degradation and unmasking the nuclear localisation signal of the p65 (RelA)/p50 heterodimer. In the nucleus p65/p50 transactivates the inflammatory programme (TNF, IL-6, IL-1β, IL-12p40, CXCL1, CCL2, iNOS, COX-2), the survival programme (Bcl-2, Bcl-xL, XIAP) and the endothelial adhesion programme (ICAM-1, VCAM-1). Two negative feedback loops shut it down: resynthesised IκBα re-sequesters p65/p50, and the p65-induced deubiquitinase A20 (TNFAIP3), together with CYLD, strips the K63/M1 chains from RIPK1, TRAF6 and NEMO.
Non-canonical arm and the In Vivo opportunity. A distinct set of TNF-receptor superfamily members — CD40, OX40, 4-1BB, LTβR, BAFF-R and RANK — triggers degradation of the TRAF3–cIAP complex that constitutively destroys NIK (MAP3K14). Stabilised NIK phosphorylates IKKα homodimers, which process the p100 (NFKB2) precursor to p52; p52/RelB then drives lymphoid organogenesis and B-cell survival via CCL19 and CCL21, and osteoclastogenesis downstream of RANKL. Because so many of these entry points are surface receptors and secreted cytokines, this is the pathway the Assay Genie In Vivo low-endotoxin range addresses most directly: anti-TNF, anti-TNFR1, anti-TNFR2, anti-IL-1β, anti-IL-1R, anti-CD40, anti-OX40, anti-4-1BB, anti-RANKL, anti-CD3 and anti-CD28 all perturb this map in vivo, while ELISA kits quantify every intracellular node and secreted output. For research use only; not for diagnostic or therapeutic procedures.
Every protein node links to a product — In Vivo antibody, ELISA kit or research antibody.