p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs
Abstract 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...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2022-12-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-01293-x |
| _version_ | 1797973792659603456 |
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| author | Gai Yamashita Naoharu Takano Hiromi Kazama Kiyoaki Tsukahara Keisuke Miyazawa |
| author_facet | Gai Yamashita Naoharu Takano Hiromi Kazama Kiyoaki Tsukahara Keisuke Miyazawa |
| author_sort | Gai Yamashita |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T04:08:47Z |
| format | Article |
| id | doaj.art-9e6edb9a15e24e839ad03cd07c6712da |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-11T04:08:47Z |
| publishDate | 2022-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-9e6edb9a15e24e839ad03cd07c6712da2023-01-01T12:13:09ZengNature Publishing GroupCell Death Discovery2058-77162022-12-018111110.1038/s41420-022-01293-xp53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugsGai Yamashita0Naoharu Takano1Hiromi Kazama2Kiyoaki Tsukahara3Keisuke Miyazawa4Department of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hospital, Shinjuku-kuDepartment of Biochemistry, Tokyo Medical University, Shinjuku-kuDepartment of Biochemistry, Tokyo Medical University, Shinjuku-kuDepartment of Otorhinolaryngology, Head and Neck Surgery, Tokyo Medical University Hospital, Shinjuku-kuDepartment of Biochemistry, Tokyo Medical University, Shinjuku-kuAbstract 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.https://doi.org/10.1038/s41420-022-01293-x |
| spellingShingle | Gai Yamashita Naoharu Takano Hiromi Kazama Kiyoaki Tsukahara Keisuke Miyazawa p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs Cell Death Discovery |
| title | p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs |
| title_full | p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs |
| title_fullStr | p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs |
| title_full_unstemmed | p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs |
| title_short | p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to DNA-damaging drugs |
| title_sort | p53 regulates lysosomal membrane permeabilization as well as cytoprotective autophagy in response to dna damaging drugs |
| url | https://doi.org/10.1038/s41420-022-01293-x |
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