Your browser doesn't support javascript.
loading
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.
Choi, Hye Yeon; Zhu, Yicheng; Zhao, Xuyao; Mehta, Simran; Hernandez, Juan Carlos; 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.
Affiliation
  • Choi HY; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Zhu Y; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Zhao X; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Mehta S; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Hernandez JC; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Lee JJ; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Kou Y; Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
  • Machida R; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Giacca M; International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
  • Del Sal G; Department of Life Sciences, University of Trieste, 34127, Trieste, Italy.
  • Ray R; International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park-Padriciano, Trieste, Italy.
  • Eoh H; IFOM ETS, The AIRC Institute of Molecular Oncology, Milan, Italy.
  • Tahara SM; Saint Louis University, School of Medicine, St Louis, MO, USA.
  • Chen L; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Tsukamoto H; Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA, USA.
  • Machida K; Viterbi School of Engineering, University of Southern California, Los Angeles, CA, USA.
Exp Mol Med ; 56(2): 461-477, 2024 Feb.
Article in En | MEDLINE | ID: mdl-38409448
ABSTRACT
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 (AlbCreERT2;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.
Subject(s)
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ubiquitin-Protein Ligases / Mitochondria Limits: Animals / Humans Language: En Journal: Exp Mol Med Journal subject: BIOLOGIA MOLECULAR / BIOQUIMICA Year: 2024 Type: Article Affiliation country: United States
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Ubiquitin-Protein Ligases / Mitochondria Limits: Animals / Humans Language: En Journal: Exp Mol Med Journal subject: BIOLOGIA MOLECULAR / BIOQUIMICA Year: 2024 Type: Article Affiliation country: United States