The Mechanism Of Autophagy Regulation Of Apoptosis

Apoptosis,programmed cell death to control cell survival,and autophagy,conserved self-eating process to maintain cellular homeostasis,Apoptosis and autophagy mutually regulate various cellular physiological and pathological processes.The crosstalk between autophagy and apoptosis is multifaceted and complicated.Generally apoptosis-associated Caspase activation blocks the autophagic process andautophagy shuts off the induction of apoptosis.Elucidating the molecular mechanism of their crosstalk will advance the therapeutic applications of autophagy for treating cancer and other diseases.Here,we report that autophagy regulates apoptosis by targeting NOXA for degradation.Inhibiting autophagy increases NOXA protein levels byextending the protein half-life.NOXA accumulation effectively suppresses tumor cell growth by inducing apoptosis,which is further enhanced when p53 is present.Mechanistically,NOXA is hijacked by p62 as autophagic cargo,and its three lysine residues at the C-terminus are necessary for NOXA degradation in lysosomes.Taken together,our study demonstrates that NOXA serves as a bridge in the crosstalk between autophagy and apoptosis and implies that autophagy inhibitors could be an effective therapy for cancer,especially wild-type p53-containing cancer.