Fig. 2

Main relopathies classified according to pathophysiology. Cytokine receptor dimerization induced by its specific ligand (e.g., TNFα) initiates canonical NF-κB pathway signaling. The activation of cytokine receptor intracellular signaling is mediated by the activation of the IKK complex, which is composed of three subunits: α, β, and g (a.k.a. NEMO). This process may be modulated by different proteins in a cascade of ubiquitination events: A20, OTULIN, HOIL-1 and HOIP. The activated IKK complex phosphorylates IκB, which signals its degradation and releases NF-κB1, a protein dimer composed of p50 and p65 (a.k.a. RelA). NF-κB1 may also be activated by intracellular pattern recognition receptors, such as NOD2, and directly by NLRP12. As a potent proinflammatory transcription factor, NF-κB1 induces cytokine (such as IL-1, IL-6 and TNFα) and proliferation-related genes. TRAPS involves intracellular ROS production induced by the accumulation of misfolded mutated TNFR1 in the ER in a process known as the unfolded protein response, culminating in MAPK activation. Red squares depict the main syndromes and their respective molecular targets classified as gain-of-function (continuous line) and loss-of-function (dashed line)-causing mutations. ER (endoplasmic reticulum); HA20 (haploinsufficiency of A20); HOIL-1 (Heme-oxidized IRP2 ubiquitin ligase 1); HOIP (HOIL-1 interacting protein); HOIL-1 def (HOIL-1 deficiency); HOIP def (HOIP deficiency); IκB (inhibitor of NF-κB); IKK (IκB kinase kinase); MAPK (mitogen-activated protein kinase); IL-1 (interleukin 1); IL-6 (interleukin 6); NEMO (NF-κB essential modulator); NF-κB1 (nuclear factor κB1); NLRP12 (NACHT, LRR and PYD domains-containing protein 2); NLRP12-AID (NLRP12-associated autoinflammatory disease); NOD2 (nucleotide-binding oligomerization domain containing 2); ORAS (OTULIN-related autoinflammatory syndrome); OTULIN (OTU deubiquitinase with linear linkage specificity); PGA/BS (pediatric granulomatous arthritis/Blau syndrome); ROS (reactive oxygen species); TNFα (tumor necrosis factor α); TNFR1 (TNFα receptor 1); TRAPS (tumor necrosis factor receptor-associated periodic syndrome)