Fig. 2

Canonical and non-canonical activation of NLRP3. NLRP3 (NOD-, LRR- and pyrin domain-containing 3) needs additional cofactors for the processing of interleukin-1β (IL-1β). MyD88/IRAK1/IRAK4 or TRIF activates TRAF6, which, in turn, catalyze the formation of a K63-linked polyubiquitin chain on TRAF6, itself. The polyubiquitin chain acts as a scaffold, recruiting TAK1 and its binding proteins, which, in turn, leads to IKK-α/β activation. Activated IKKα/β specifically phosphorylates IkBα, resulting in IkBα degradation and NF-kB translocation into the nucleus. TRIF can also recruit TRAF3 to activate TBK1 and IKKi. TBK1/IKKi directly phosphorylates IRF3/7 to activate type IFN I signaling pathway. Various molecules positively (green arrow) or negatively (red blunt arrow) regulate TLR-induced signaling pathways. TAK1 (transforming growth factor 1 activating kinase) restrains both NLRP3 priming and activation. TAK1 activity restricts NLRP3 priming by limiting spontaneous activation of receptor protein kinase 1 (RIP1). MyD88- myeloid differentiation primary response 88; IRAK1—Interleukin-1 receptor-associated kinase 1; IRAK4- Interleukin-1 receptor-associated kinase 4; TRIF- TIR-domain-containing adapter-inducing interferon-β; TRAF6- TNF receptor associated factor 6; TRAF3- TNF receptor associated factor 3; TBK1-TANK binding kinase 1