NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells
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| Názov: | NOTCH localizes to mitochondria through the TBC1D15-FIS1 interaction and is stabilized via blockade of E3 ligase and CDK8 recruitment to reprogram tumor-initiating cells |
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| Autori: | Hye Yeon Choi, Yicheng Zhu, Xuyao Zhao, Simran Mehta, Juan Carlos Hernandez, Jae-Jin Lee, Yi Kou, Risa Machida, Mauro Giacca, Giannino Del Sal, Ratna Ray, Hyungjin Eoh, Stanley M. Tahara, Lin Chen, Hidekazu Tsukamoto, Keigo Machida |
| Prispievatelia: | Choi, Hye Yeon, Zhu, Yicheng, Zhao, Xuyao, Mehta, Simran, Hernandez, Juan Carlo, Lee, Jae-Jin, Kou, Yi, Machida, Risa, Giacca, Mauro, Del Sal, Giannino, Ray, Ratna, Eoh, Hyungjin, Tahara, Stanley M., Chen, Lin, Tsukamoto, Hidekazu, Machida, Keigo |
| Zdroj: | Exp Mol Med Experimental and Molecular Medicine, Vol 56, Iss 2, Pp 461-477 (2024) |
| Informácie o vydavateľovi: | Springer Science and Business Media LLC, 2024. |
| Rok vydania: | 2024 |
| Predmety: | 0301 basic medicine, Chromatin Immunoprecipitation, cancer, tumor-initiating cells, NOTCH, prolyl isomerase Pin1, Ubiquitin-Protein Ligases, QD415-436, Biochemistry, Article, tumor-initiating cell, Mitochondrial Proteins, Mice, 03 medical and health sciences, Humans, Animals, Phosphorylation, 0303 health sciences, GTPase-Activating Proteins, Membrane Proteins, Cyclin-Dependent Kinase 8, Cyclin-Dependent Kinases, Mitochondria, Disease Models, Animal, Mitochondrial Membranes, Medicine |
| Popis: | The P53-destabilizing TBC1D15-NOTCH protein interaction promotes self-renewal of tumor-initiating stem-like cells (TICs); however, the mechanisms governing the regulation of this pathway have not been fully elucidated. Here, we show that TBC1D15 stabilizes NOTCH and c-JUN through blockade of E3 ligase and CDK8 recruitment to phosphodegron sequences. Chromatin immunoprecipitation (ChIP-seq) analysis was performed to determine whether TBC1D15-dependent NOTCH1 binding occurs in TICs or non-TICs. The TIC population was isolated to evaluate TBC1D15-dependent NOTCH1 stabilization mechanisms. The tumor incidence in hepatocyte-specific triple knockout (Alb::CreERT2;Tbc1d15Flox/Flox;Notch1Flox/Flox;Notch2Flox/Flox;HCV-NS5A) Transgenic (Tg) mice and wild-type mice was compared after being fed an alcohol-containing Western diet (WD) for 12 months. The NOTCH1-TBC1D15-FIS1 interaction resulted in recruitment of mitochondria to the perinuclear region. TBC1D15 bound to full-length NUMB and to NUMB isoform 5, which lacks three Ser phosphorylation sites, and relocalized NUMB5 to mitochondria. TBC1D15 binding to NOTCH1 blocked CDK8- and CDK19-mediated phosphorylation of the NOTCH1 PEST phosphodegron to block FBW7 recruitment to Thr-2512 of NOTCH1. ChIP-seq analysis revealed that TBC1D15 and NOTCH1 regulated the expression of genes involved in mitochondrial metabolism-related pathways required for the maintenance of TICs. TBC1D15 inhibited CDK8-mediated phosphorylation to stabilize NOTCH1 and protect it from degradation The NUMB-binding oncoprotein TBC1D15 rescued NOTCH1 from NUMB-mediated ubiquitin-dependent degradation and recruited NOTCH1 to the mitochondrial outer membrane for the generation and expansion of liver TICs. A NOTCH-TBC1D15 inhibitor was found to inhibit NOTCH-dependent pathways and exhibited potent therapeutic effects in PDX mouse models. This unique targeting of the NOTCH-TBC1D15 interaction not only normalized the perinuclear localization of mitochondria but also promoted potent cytotoxic effects against TICs to eradicate patient-derived xenografts through NOTCH-dependent pathways. |
| Druh dokumentu: | Article Other literature type |
| Popis súboru: | application/pdf |
| Jazyk: | English |
| ISSN: | 2092-6413 |
| DOI: | 10.1038/s12276-024-01174-6 |
| Prístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/38409448 https://doaj.org/article/cce91a31632d430a830e45249520ef25 https://www.nature.com/articles/s12276-024-01174-6 https://hdl.handle.net/11368/3100044 https://pmc.ncbi.nlm.nih.gov/articles/pmid/38409448/ https://www.nature.com/articles/s12276-024-01174-6 https://doi.org/10.1038/s12276-024-01174-6 https://hdl.handle.net/11368/3100044 |
| Rights: | CC BY |
| Prístupové číslo: | edsair.doi.dedup.....d8e0236faff3c01355b6ed5b28ca774d |
| Databáza: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | The P53-destabilizing TBC1D15-NOTCH protein interaction promotes self-renewal of tumor-initiating stem-like cells (TICs); however, the mechanisms governing the regulation of this pathway have not been fully elucidated. Here, we show that TBC1D15 stabilizes NOTCH and c-JUN through blockade of E3 ligase and CDK8 recruitment to phosphodegron sequences. Chromatin immunoprecipitation (ChIP-seq) analysis was performed to determine whether TBC1D15-dependent NOTCH1 binding occurs in TICs or non-TICs. The TIC population was isolated to evaluate TBC1D15-dependent NOTCH1 stabilization mechanisms. The tumor incidence in hepatocyte-specific triple knockout (Alb::CreERT2;Tbc1d15Flox/Flox;Notch1Flox/Flox;Notch2Flox/Flox;HCV-NS5A) Transgenic (Tg) mice and wild-type mice was compared after being fed an alcohol-containing Western diet (WD) for 12 months. The NOTCH1-TBC1D15-FIS1 interaction resulted in recruitment of mitochondria to the perinuclear region. TBC1D15 bound to full-length NUMB and to NUMB isoform 5, which lacks three Ser phosphorylation sites, and relocalized NUMB5 to mitochondria. TBC1D15 binding to NOTCH1 blocked CDK8- and CDK19-mediated phosphorylation of the NOTCH1 PEST phosphodegron to block FBW7 recruitment to Thr-2512 of NOTCH1. ChIP-seq analysis revealed that TBC1D15 and NOTCH1 regulated the expression of genes involved in mitochondrial metabolism-related pathways required for the maintenance of TICs. TBC1D15 inhibited CDK8-mediated phosphorylation to stabilize NOTCH1 and protect it from degradation The NUMB-binding oncoprotein TBC1D15 rescued NOTCH1 from NUMB-mediated ubiquitin-dependent degradation and recruited NOTCH1 to the mitochondrial outer membrane for the generation and expansion of liver TICs. A NOTCH-TBC1D15 inhibitor was found to inhibit NOTCH-dependent pathways and exhibited potent therapeutic effects in PDX mouse models. This unique targeting of the NOTCH-TBC1D15 interaction not only normalized the perinuclear localization of mitochondria but also promoted potent cytotoxic effects against TICs to eradicate patient-derived xenografts through NOTCH-dependent pathways. |
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| ISSN: | 20926413 |
| DOI: | 10.1038/s12276-024-01174-6 |