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Protease-controlled secretion and display of intercellular signals

Author

Listed:
  • Alexander E. Vlahos

    (Stanford University)

  • Jeewoo Kang

    (Stanford University)

  • Carlos A. Aldrete

    (Stanford University)

  • Ronghui Zhu

    (California Institute of Technology)

  • Lucy S. Chong

    (California Institute of Technology)

  • Michael B. Elowitz

    (California Institute of Technology)

  • Xiaojing J. Gao

    (Stanford University
    Stanford University)

Abstract

To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. If such regulations are at the protein level, there are additional advantages, including compact delivery and direct interactions with endogenous signaling pathways. Here we create a modular, generalizable design called Retained Endoplasmic Cleavable Secretion (RELEASE), with engineered proteins retained in the endoplasmic reticulum and displayed/secreted in response to specific proteases. The design allows functional regulation of multiple synthetic and natural proteins by synthetic protease circuits to realize diverse signal processing capabilities, including logic operation and threshold tuning. By linking RELEASE to additional sensing and processing circuits, we can achieve elevated protein secretion in response to “undruggable” oncogene KRAS mutants. RELEASE should enable the local, programmable delivery of intercellular cues for a broad variety of fields such as neurobiology, cancer immunotherapy and cell transplantation.

Suggested Citation

  • Alexander E. Vlahos & Jeewoo Kang & Carlos A. Aldrete & Ronghui Zhu & Lucy S. Chong & Michael B. Elowitz & Xiaojing J. Gao, 2022. "Protease-controlled secretion and display of intercellular signals," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-28623-y
    DOI: 10.1038/s41467-022-28623-y
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    References listed on IDEAS

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    1. Bastiaan C. Buddingh’ & Janneke Elzinga & Jan C. M. van Hest, 2020. "Intercellular communication between artificial cells by allosteric amplification of a molecular signal," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    2. Velia Siciliano & Breanna DiAndreth & Blandine Monel & Jacob Beal & Jin Huh & Kiera L Clayton & Liliana Wroblewska & AnneMarie McKeon & Bruce D. Walker & Ron Weiss, 2018. "Engineering modular intracellular protein sensor-actuator devices," Nature Communications, Nature, vol. 9(1), pages 1-7, December.
    3. Timothy H. Tran & Albert H. Chan & Lucy C. Young & Lakshman Bindu & Chris Neale & Simon Messing & Srisathiyanarayanan Dharmaiah & Troy Taylor & John-Paul Denson & Dominic Esposito & Dwight V. Nissley , 2021. "KRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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    5. Chad M. Glen & Todd C. McDevitt & Melissa L. Kemp, 2018. "Author Correction: Dynamic intercellular transport modulates the spatial patterning of differentiation during early neural commitment," Nature Communications, Nature, vol. 9(1), pages 1-1, December.
    6. Elisa Pedone & Lorena Postiglione & Francesco Aulicino & Dan L. Rocca & Sandra Montes-Olivas & Mahmoud Khazim & Diego Bernardo & Maria Pia Cosma & Lucia Marucci, 2019. "A tunable dual-input system for on-demand dynamic gene expression regulation," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
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    Cited by:

    1. Mohamed Mahameed & Pengli Wang & Shuai Xue & Martin Fussenegger, 2022. "Engineering receptors in the secretory pathway for orthogonal signalling control," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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