The multiunit Cullin (CUL)-RING E3 ligase (CRL) controls diverse biological 
processes by targeting a mass of substrates for ubiquitination and degradation, 
whereas its dysfunction causes carcinogenesis. Post-translational neddylation of 
CUL, a process triggered by the NEDD8-activating enzyme E1 subunit 1 (NAE1), is 
required for CRL activation. Recently, MLN4924 was discovered via a 
high-throughput screen as a specific NAE1 inhibitor and first-in-class 
anticancer drug. By blocking CUL neddylation, MLN4924 inactivates CRL and causes 
the accumulation of CRL substrates that trigger cell cycle arrest, senescence 
and/or apoptosis to suppress the growth of cancer cells in vitro and in vivo. 
Recently, we found that MLN4924 also triggers protective autophagy in response 
to CRL inactivation. MLN4924-induced autophagy is attributed partially to the 
inhibition of mechanistic target of rapamycin (also known as mammalian target of 
rapamycin, MTOR) activity by the accumulation of the MTOR inhibitory protein 
DEPTOR, as well as reactive oxygen species (ROS)-induced stress. Moreover, the 
blockage of autophagy response enhances apoptosis in MLN4924-treated cells. 
Together, our findings not only reveal autophagy as a novel cellular response to 
CRL inactivation by MLN4924, but also provide a piece of proof-of-concept 
evidence for the combination of MLN4924 with autophagy inhibitors to enhance 
therapeutic efficacy.