FBXO42 facilitates Notch signaling activation and global chromatin relaxation by promoting K63-linked polyubiquitination of RBPJ

  • Sci Adv. 2022 Sep 23;8(38):eabq4831. doi: 10.1126/sciadv.abq4831.
Hua Jiang  1  2  3 ,  Weixiang Bian  1  2  3 ,  Yue Sui  1  2  3 ,  Huanle Li  2  3 ,  Han Zhao  2  3 ,  Wenqi Wang  4 ,  Xu Li  1  2  3
Affiliations
  • 1. Fudan University, Shanghai 310018, China.
  • 2. Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China.
  • 3. Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China.
  • 4. Department of Developmental and Cell Biology, University of California, Irvine, Irvine, CA 92697, USA.
PMID: 36129980 DOI: 10.1126/sciadv.abq4831
Abstract

Dysregulation of the Notch-RBPJ (recombination signal-binding protein of immunoglobulin kappa J region) signaling pathway has been found associated with various human diseases including cancers; however, precisely how this key signaling pathway is fine-tuned via its interactors and modifications is still largely unknown. In this study, using a proteomic approach, we identified F-box only protein 42 (FBXO42) as a previously unidentified RBPJ interactor. FBXO42 promotes RBPJ polyubiquitination on lysine-175 via lysine-63 linkage, which enhances the association of RBPJ with chromatin remodeling complexes and induces a global chromatin relaxation. Genetically depleting FBXO42 or pharmacologically targeting its E3 Ligase activity attenuates the Notch signaling-related leukemia development in vivo. Together, our findings not only revealed FBXO42 as a critical regulator of the Notch pathway by modulating RBPJ-dependent global chromatin landscape changes but also provided insights into the therapeutic intervention of the Notch pathway for leukemia treatment.

Products