p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs

• Published in: Cell death discovery Vol. 8; no. 1; pp. 502 - 11
• Main Authors: Yamashita, Gai, Takano, Naoharu, Kazama, Hiromi, Tsukahara, Kiyoaki, Miyazawa, Keisuke
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.12.2022; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/67/1059/2326; 631/67/1059/99; 631/80/39/2346; 631/80/82; Antibiotics; Apoptosis; Autophagy; Azithromycin; Biochemistry; Biomedical and Life Sciences; Carboplatin; Cathepsins; Cell Biology; Cell Cycle Analysis; Cell death; Cholesterol; Cytoplasm; Deoxyribonucleic acid; DNA; DNA damage; Doxorubicin; Drugs; Etoposide; Hydroxychloroquine; Life Sciences; Lysosomes; Macromolecules; Niemann-Pick disease; Npc1 protein; Organelles; Stem Cells; TOR protein
• ISSN: 2058-7716; 2058-7716
• DOI: 10.1038/s41420-022-01293-x

Lysosomes are single-membraned organelles that mediate the intracellular degradation of macromolecules. Various stress can induce lysosomal membrane permeabilization (LMP), translocating intralysosomal components, such as cathepsins, to the cytoplasm, which induces lysosomal-dependent cell death (LDCD). This study reports that p53 regulates LMP in response to DNA-damaging drugs. Treating wild-type TP53 A549 cells with DNA-damaging drugs (namely, doxorubicin, carboplatin, and etoposide) induced LMP and accelerated cell death more rapidly than treating TP53 -knockout (KO) A549 cells. This suggested p53-dependent LMP and LDCD induction in response to DNA damage. LMP was induced by p53-dependent BID upregulation and activation, followed by translocation of truncated BID to lysosomes. Simultaneously, autophagy for damaged lysosome elimination (lysophagy) was activated via the p53–mTOR–TEFB/TFE3 pathways in response to DNA damage. These data suggested the dichotomous nature of p53 for LMP regulation; LMP induction and repression via the p53–BID axis and p53–mTOR–TFEB/TFE3 pathway, respectively. Blocking autophagy with hydroxychloroquine or azithromycin as well as ATG5 KO enhanced LMP and LDCD induction after exposure to DNA-damaging drugs. Furthermore, lysosomal membrane stabilization using U18666A, a cholesterol transporter Niemann-Pick disease C1 (NPC1) inhibitor, suppressed LMP as well as LDCD in wild-type TP53 , but not in TP53 -KO, A549 cells. Thus, LMP is finely regulated by TP53 after exposure to DNA-damaging drugs.