A spatially defined human Notch receptor interaction network reveals Notch intracellular storage and Ataxin-2-mediated fast recycling
Weixiang Bian,
Hua Jiang,
Luxia Yao,
Wanyu Hao,
Lianfeng Wu,
Xu Li
Affiliations
Weixiang Bian
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China
Hua Jiang
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China
Luxia Yao
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
Wanyu Hao
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China
Lianfeng Wu
Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China; Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China; Corresponding author
Xu Li
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou 310024, Zhejiang, China; Westlake Laboratory of Life Sciences and Biomedicine, Hangzhou 310024, Zhejiang, China; Institute of Biology, Westlake Institute for Advanced Study, Hangzhou 310024, Zhejiang, China; Corresponding author
Summary: The Notch signaling pathway controls cell growth, differentiation, and fate decisions. Dysregulation of Notch signaling has been linked to various human diseases. Notch receptor resides in multiple cellular compartments, and its translocation plays a central role in pathway activation. However, the spatial regulation of Notch receptor functions remains largely elusive. Using TurboID-based proximity labeling followed by affinity purification and mass spectrometry, we establish a spatially defined human Notch receptor interaction network. Notch receptors interact with different proteins in distinct subcellular compartments to perform specific cellular functions. This spatially defined interaction network also reveals that a large fraction of NOTCH is stored at the endoplasmic reticulum (ER)-Golgi intermediate compartment and recruits Ataxin-2-dependent recycling machinery for rapid recycling, Notch signaling activation, and leukemogenesis. Our work provides insights into dynamic Notch receptor complexes with exquisite spatial resolution, which will help in elucidating the detailed regulation of Notch receptors and highlight potential therapeutic targets for Notch-related pathogenesis.
