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Engineered proteins with sensing and activating modules for automated reprogramming of cellular functions.
Jie Sun1,2,3, Lei Lei4, Chih-Ming Tsai5
1Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, IL, 61801, USA.
Nature Communications
|September 9, 2017
Summary
Scientists developed an integrated sensing and activating protein (iSNAP) to visualize molecular signals and control cellular functions. This tool rewires cell signaling pathways, enhancing phagocytosis for potential therapeutic applications.
Area of Science:
- Molecular Biology
- Cell Biology
- Immunology
Background:
- Protein-based biosensors and activators are crucial for visualizing molecular signals and manipulating cellular functions.
- Existing tools often focus on either sensing or activation, limiting integrated control.
- The CD47-SIRPα axis typically mediates anti-phagocytic signals, hindering tumor cell clearance.
Purpose of the Study:
- To engineer a novel protein-based tool, iSNAP, that integrates sensing and activation functionalities.
- To demonstrate iSNAP's capability in detecting tyrosine phosphorylation and activating specific enzymes.
- To reprogram the CD47-SIRPα axis in macrophages to enhance phagocytosis of tumor cells.
Main Methods:
- Modular assembly of protein domains to create the iSNAP system.
- Design of Shp2-iSNAP and Syk-iSNAP prototypes for specific signaling pathways.
- Fusion of iSNAP constructs to the SIRPα receptor in macrophages.
- Analysis of SIRPα phosphorylation and phagocytic activity upon CD47 engagement.
Main Results:
- Developed iSNAP, a single protein molecule combining sensing and activation.
- Shp2-iSNAP successfully detected SIRPα phosphorylation and activated Shp2 phosphatase.
- Engineered macrophages exhibited enhanced phagocytosis of opsonized tumor cells by rewiring the CD47-SIRPα axis.
- Syk-iSNAP demonstrated the ability to activate Syk kinase, promoting phagocytosis.
Conclusions:
- iSNAP offers a versatile platform for sensing molecular signals and executing automated cellular responses.
- Reprogramming the CD47-SIRPα axis via iSNAP enhances macrophage-mediated phagocytosis.
- This approach holds promise for developing targeted therapeutics by controlling cellular functions.
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