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.
Highlights
To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins
To take cancer immunotherapy as an example, there an ideal application would be introducing a protein circuit that sense the cancerous state of a cell, secrete immunostimulatory signals with temporal and quantitative precision to mobilize the immune system while lysing the cell, and turn these cells into vaccines against other cancerous cells
This study demonstrates a protein-level control module to directly regulate protein secretion that is compatible with pre-existing protein components to program therapeutic circuits for cancer immunotherapy and transplantation in the future
Summary
To program intercellular communication for biomedicine, it is crucial to regulate the secretion and surface display of signaling proteins. To take cancer immunotherapy as an example, there an ideal application would be introducing a protein circuit that sense the cancerous state of a cell, secrete immunostimulatory signals with temporal and quantitative precision to mobilize the immune system while lysing the cell, and turn these cells into vaccines against other cancerous cells This would avoid the toxic effects associated with the systemic delivery of immunomodulating proteins[19,20], and match the complex, dynamic immune process we are trying to control[21]. To place ER retention under protease control, we engineered the modular Retained Endoplasmic Cleavable Secretion (RELEASE) platform, compatible with both protein secretion and the surface display of membrane proteins. This study demonstrates a protein-level control module to directly regulate protein secretion that is compatible with pre-existing protein components to program therapeutic circuits for cancer immunotherapy and transplantation in the future
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