Autophagy regulates apoptosis by targeting NOXA for degradation

Biochimica Et Biophysica Acta. Molecular Cell Research
Jingchao WangYongchao Zhao

Abstract

Apoptosis and autophagy mutually regulate various cellular physiological and pathological processes. The crosstalk between autophagy and apoptosis is multifaceted and complicated. Elucidating the molecular mechanism of their crosstalk will advance the therapeutic applications of autophagy for treating cancer and other diseases. NOXA, a BH3-only member of the BCL-2 family, was reported to induce apoptosis and promote autophagy. Here, we report that autophagy regulates apoptosis by targeting NOXA for degradation. Inhibiting autophagy increases NOXA protein levels by extending 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.

Citations

Jul 28, 2020·Pharmaceuticals·Angel Escamilla-RamírezCristina Trejo-Solís
Nov 21, 2019·Molecular Cancer Therapeutics·Ximena Rosas-PlazaSteven de Jong
Apr 16, 2020·Anti-cancer Agents in Medicinal Chemistry·Nkune W NkuneHeidi Abrahamse

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