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A programmable targeted protein-degradation platform for versatile applications in mammalian cells and mice.

Author information

Affiliations

  • 1. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Centre, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
      Authors
    • Ma X 1
    • Qiao L 1
    • Wan H 1
    • Liu X 1
    • Wu J 1
    • Niu L 1
    • Wu M 1
    • Wang X 1
    • Ye H 1
    (9 authors)
  • 2. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Centre, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing 401120, China.
      Authors
    • Yin J 2
    (1 author)
  • 3. Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Biomedical Synthetic Biology Research Centre, Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; Wuhu Hospital, Health Science Center, East China Normal University, Wuhu City 241001, China.
      Authors
    • Zhou Y 3
    (1 author)

ORCIDs linked to this article

Molecular Cell, 12 Mar 2024, 84(8):1585-1600.e7
https://doi.org/10.1016/j.molcel.2024.02.019 PMID: 38479385 

Abstract 

Myriad physiological and pathogenic processes are governed by protein levels and modifications. Controlled protein activity perturbation is essential to studying protein function in cells and animals. Based on Trim-Away technology, we screened for truncation variants of E3 ubiquitinase Trim21 with elevated efficiency (ΔTrim21) and developed multiple ΔTrim21-based targeted protein-degradation systems (ΔTrim-TPD) that can be transfected into host cells. Three ΔTrim-TPD variants are developed to enable chemical and light-triggered programmable activation of TPD in cells and animals. Specifically, we used ΔTrim-TPD for (1) red-light-triggered inhibition of HSV-1 virus proliferation by degrading the packaging protein gD, (2) for chemical-triggered control of the activity of Cas9/dCas9 protein for gene editing, and (3) for blue-light-triggered degradation of two tumor-associated proteins for spatiotemporal inhibition of melanoma tumor growth in mice. Our study demonstrates that multiple ΔTrim21-based controllable TPD systems provide powerful tools for basic biology research and highlight their potential biomedical applications.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/j.molcel.2024.02.019

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Funding 

Funders who supported this work.

National Natural Science Foundation of China