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. 2019 May 16;10:1107. doi: 10.3389/fimmu.2019.01107

Figure 6.

Figure 6

The regulatory mechanisms of the IL-17–TRAF6 pathway. TRAF2 and TRAF5 interact with ACT1 and activate downstream MAPK signaling. The TRAF2/5 binding with ACT1 is dependent on ACT1 S311 phosphorylation by IKKε. IKKε and TBK1 can also be involved in the suppression of the association of ACT1–TRAF6 binding. Hsp90 is a chaperone protein of ACT1. The binding between Hsp90 and ACT1 is required for the IL-17 signaling and is dependent on ACT1 D19. SCFβ−TrCP E3 ubiquitin ligase complexes are involved in the K48-linked polyubiquitination and degradation of ACT1. TRAF3 is expected to inhibit IL-17 signaling by competing with ACT1 to interact with IL-17R. TRAF4 is also suggested to be a negative regulator for IL-17 signaling, probably due to the competition of TRAF4 with TRAF6 for the interaction with ACT1. Peli1 opposes to TRAF3, by promoting TRAF6-induced K63-linked ubiquitination of c-IAP, which then ubiquitinates TRAF3 with K48 linkage, resulting in TRAF3 proteasomal degradation. NDR1 interferes TRAF3–TRAF6 interaction. A20 is a negative regulator for ubiquitin signaling via dual activity: (1) deubiquitinase activity to K63-linked chains and (2) K48-linked ubiquitinase activity mediating proteasomal degradation of substrate signaling molecules. ABIN1 promotes A20 activity. CYLD and USP25 are other deubiquitinases. C/EBP has both stimulatory and regulatory roles in the transcription of IL-17-response genes. ABIN1, A20 binding and inhibitor of NF-κB-1; ACT1, NF-κB activator 1; BCL10, B-cell lymphoma/leukemia 10; CARD, caspase recruitment domain-containing protein; C/EBP, CCAAT/enhancer binding protein; Hsp, heat shock protein; IKK, IκB kinase; MALT1, mucosa associated lymphoid tissue lymphoma translocation gene 1; NDR1, Nuclear Dbf2-related kinase 1; NEMO, NF-κB essential modulator; NF-κB, nuclear factor κB; SCFβ−TrCP, Skp1-cullin-1-F-box protein β-transducin repeat-containing protein; TAB, TAK1 binding protein; TAK1, transforming growth factor-β-activated kinase 1; TBK1, TANK-binding kinase 1; TRAF, tumor necrosis factor receptor associated factor; USP25, ubiquitin-specific protease 25.