Fig. 3

The mechanism by which A20 regulates arthritis. (a) In the TNF-induced NF-κB pathway, A20 can impair IKK complex activation, thus opposing the activation of NF-κB. Moreover, A20 removes lysine-63 (K63)-linked ubiquitin chains from RIPK1 and TNFR1 and adds K48-linked ubiquitin to RIPK1, thus targeting RIPK1 for proteasomal degradation and leading to dissociation of a RIPK1-containing complex from the membrane; these processes eventually block NF-κB-mediated promotion of cell survival. Degradation of RIPK1 avoids procaspase 8-dependent apoptosis and procaspase 8-mediated cleavage of pro-IL-1β. Additionally, phosphorylation of RIPK3 in the RIPK3-dependent RIPK1-RIPK3 complex is suppressed when A20 is present, and RIPK1-RIPK3-MLKL-dependent necroptosis is accordingly reduced. Furthermore, A20 stabilizes the connection of the M1-linked ubiquitin chain to complex I through its ZnF7 domain to protect them from being degraded by other DUBs and avoid necroptosis. b TLR-induced NF-κB activation due to LPS and IL-1β stimulation can be interrupted by A20 by impairing IKK complex activation as described above. A20 can also remove K63 ubiquitin chains on TRAF6, thereby blocking NF-κB and preventing MAPK activation to reduce IL-17 expression. c IL-17-induced activation of NF-κB can be restricted by A20 by removing K63-linked ubiquitin chains from TRAF6 and interrupting IKK complex activation. Moreover, A20 can restrict MAPK activation. On the one hand, A20 hinders the phosphorylation of JNK, thereby restricting MAPK signaling and reducing the production of pro-inflammatory factors. On the other hand, the existence of A20 inhibits p38 MARK and PKC activity to decrease IL-17 levels to hinder further inflammatory responses mediated by IL-17. d A20 can reduce the transcription of NLRP3, ASC, procaspase 1, pro-IL-1β, and proIL-18, and this regulation relies on the activation of NF-κB and directly lowers the basal expression of NLRP3 to impair inflammatory activation, thus blocking the secretion of IL-1β and IL-18. A20 also has the ability to inhibit pyroptosis in a mechanism that is dependent on active Casp1, thereby restoring the IL-1β production process