Fig. 6.

Ubiquitination and autophagy regulation. GCA triggers TRAF6 activity to induce K63-linked ULK1 ubiquitination. ULK1 deubiquitination by USP1 is required after TRAF6-induced ULK1 ubiquitination. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis, which restrains the amplitude and duration of autophagy. TLR-mediated signaling can induce autophagy via the association of TRAF6 with the coiled-coil domain of Beclin1 and Beclin1 ubiquitination. A20 reduces the extent of K63-linked Beclin1 ubiquitination. PRDX1 binds to TRAF6 to inhibit K63-linked-ubiquitination of TRAF6, leading to reduced TRAF6 ubiquitin-ligase activity, which fails to activate Beclin1. KLHL20, UBE3C and TRABID reciprocally regulate K29/48-branched ubiquitination of VPS34, mediating its proteasome degradation. TRAF6 polyubiquitinates LC3B and promotes LC3B-ATG7 complex formation to drive selective autophagic CTNNB1 degradation. HACE1 ubiquitinates OPTN with K27 and K48 ubiquitin linkages and on multiple lysine residues of OPTN containing K193. OPTN ubiquitination at K193 promotes the interaction with p62 to activate autophagy. USP8 deubiquitinates p62 by removing the K11-linked ubiquitin chains from p62, and the deubiquitinated site is principally located at K420 site, which leads to p62 reduced degradation and autophagy flux. p62 can be also ubiquitinated by Keap1/Cullin3 to promote p62’s association with LC3 and autophagy