Engineered proteins with sensing and activating modules for automated reprogramming of cellular functions

Jie Sun, Lei Lei, Chih-Ming Tsai, Yi Wang, Yiwen Shi, Mingxing Ouyang, Shaoying Lu, Jihye Seong, Tae-Jin Kim, Pengzhi Wang, Min Huang, Xiangdong Xu, Victor Nizet, Shu Chien () and Yingxiao Wang ()
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Jie Sun: University of Illinois at Urbana-Champaign
Lei Lei: University of California, San Diego
Chih-Ming Tsai: University of California, San Diego
Yi Wang: University of Illinois at Urbana-Champaign
Yiwen Shi: University of California, San Diego
Mingxing Ouyang: University of California, San Diego
Shaoying Lu: University of California, San Diego
Jihye Seong: University of Illinois at Urbana-Champaign
Tae-Jin Kim: University of Illinois at Urbana-Champaign
Pengzhi Wang: University of California, San Diego
Min Huang: University of Illinois at Urbana-Champaign
Xiangdong Xu: University of California, San Diego
Victor Nizet: University of California, San Diego
Shu Chien: University of California, San Diego
Yingxiao Wang: University of Illinois at Urbana-Champaign

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: Abstract Protein-based biosensors or activators have been engineered to visualize molecular signals or manipulate cellular functions. Here we integrate these two functionalities into one protein molecule, an integrated sensing and activating protein (iSNAP). A prototype that can detect tyrosine phosphorylation and immediately activate auto-inhibited Shp2 phosphatase, Shp2-iSNAP, is designed through modular assembly. When Shp2-iSNAP is fused to the SIRPα receptor which typically transduces anti-phagocytic signals from the ‘don’t eat me’ CD47 ligand through negative Shp1 signaling, the engineered macrophages not only allow visualization of SIRPα phosphorylation upon CD47 engagement but also rewire the CD47-SIRPα axis into the positive Shp2 signaling, which enhances phagocytosis of opsonized tumor cells. A second SIRPα Syk-iSNAP with redesigned sensor and activator modules can likewise rewire the CD47-SIRPα axis to the pro-phagocytic Syk kinase activation. Thus, our approach can be extended to execute a broad range of sensing and automated reprogramming actions for directed therapeutics.

Date: 2017
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DOI: 10.1038/s41467-017-00569-6

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