2. Academic Validation
  3. A K27-linked Ubiquitin Checkpoint Controls NOTCH Homeostasis

A K27-linked Ubiquitin Checkpoint Controls NOTCH Homeostasis

  • bioRxiv. 2025 Dec 19:2025.12.18.695023. doi: 10.64898/2025.12.18.695023.
Behzad Mansoori,  Ying Song,  Tian Zhang,  Zihan Zheng,  Qing Zhu,  Shun Li,  Mckenna Reale,  Christian Pangilinan,  Janvhi Suresh Machhar,  Jinghui Liang,  Jason Chang,  Young-Kwon Hong,  Gerald B Wertheim,  Maureen E Murphy,  Yong-Mi Kim,  Markus Muschen,  Michaela U Gack,  Andrew V Kossenkov,  Qin Liu,  Noam Auslander,  Iannis Aifantis,  Chintan Parekh,  Chengyu Liang
PMID: 41446230 DOI: 10.64898/2025.12.18.695023
Abstract

Cell surface receptors such as NOTCH1 must be tightly regulated to ensure developmental fidelity and prevent pathological activation. Although the proteolytic steps culminating in nuclear NOTCH1 signaling are established, how cells prevent excessive or uncontrolled activation has remained unresolved. Here we identify the autophagy-related protein UVRAG as a negative regulator of NOTCH1. Upon receptor activation, UVRAG, acting independently of Autophagy, recruits and activates the E3-ligase ITCH to catalyze K27-linked ubiquitination of membrane-tethered NOTCH1, thereby licensing ESCRT-dependent lysosomal degradation. Disruption of the UVRAG-ITCH-ESCRT axis stabilizes activated NOTCH1 intermediates and amplifies oncogenic signaling. In T-cell leukemia models driven by constitutive NOTCH1 activity, restoring UVRAG expression reinstates receptor turnover, suppresses disease progression, and improves therapeutic response. These findings define a ubiquitin-directed safeguard circuit that enforces NOTCH1 signaling homeostasis and reveals a tunable axis for intervention in NOTCH1-driven cancers.

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