Figure 1. NEDD8-activating enzyme E1 subunit 1 (NAE1) inhibitor MLN4924 triggers protective autophagy in cancer cells. CRL/SCF is a multiunit E3 ubiquitin ligase family with a CUL-RBX/ROC complex as its core structure. Post-translational neddylation of CUL is required for the activation of CRL/SCF E3 ligase. During this process, the ubiquitin-like molecule NEDD8 is transferred to CUL by NAE1, NEDD8 conjugating enzyme E2 (UBE2M/Ubc12) and the NEDD8-E3 ligase cascade. The NAE1 inhibitor MLN4924 blocks CUL neddylation and inactivates CRL/SCF to induce protective autophagy, whereas blockage of the autophagy pathway via knockdown of autophagy essential genes (such as ATG5) significantly enhances apoptosis in MLN4924-treated cells. Mechanistically, MLN4924-induced autophagy is attributed to: (a) the inhibition of MTOR activity by the accumulation of the MTOR inhibitory protein DEPTOR, which is a CRL/SCF substrate; (b) reactive oxygen species-induced stress; and (c) dysfunction of other CRL/SCF-regulated substrates and pathways to be identified. Ub, ubiquitin; N8, NEDD8; SR, substrate receptor.