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Nature communications
02 17, 2022;13 (1): 912.

Protease-controlled secretion and display of intercellular signals.

Alexander E Vlahos, Jeewoo Kang, Carlos A Aldrete, Ronghui Zhu, Lucy S Chong, Michael B Elowitz, Xiaojing J Gao
Author Information
  1. Alexander E Vlahos: Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA.
  2. Jeewoo Kang: Neurosciences Interdepartmental Program, Stanford University, Stanford, CA, 94305, USA.
  3. Carlos A Aldrete: Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA. ORCID
  4. Ronghui Zhu: Howard Hughes Medical Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA. ORCID
  5. Lucy S Chong: Howard Hughes Medical Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
  6. Michael B Elowitz: Howard Hughes Medical Institute, Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA. ORCID
  7. Xiaojing J Gao: Department of Chemical Engineering, Stanford University, Stanford, CA, 94305, USA. xjgao@stanford.edu. ORCID
PMID: 35177637 DOI: 10.1038/s41467-022-28623-y

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.

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Grants

  1. R00 EB027723/NIBIB NIH HHS

MeSH Term

Flow Cytometry
HEK293 Cells
Humans
Mutation
Peptide Hydrolases
Protein Engineering
Protein Transport
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Synthetic Biology

Chemicals

KRAS protein, human
Peptide Hydrolases
Proto-Oncogene Proteins p21(ras)
Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't
Article has an altmetric score of 63

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