Perspectives on Synthetic Protein Circuits in Mammalian Cells.

Area of Science:

• Synthetic biology
• Molecular and Cell Biology
• Biomedical Engineering

Background:

• Mammalian synthetic biology engineers cellular behaviors for therapeutic applications, including cancer immunotherapy and cell transplantation.
• Traditional synthetic biology relied on transcriptional circuits, but protein circuits offer advantages like robustness and speed.
• Understanding molecular mechanisms is crucial for programming complex cellular responses.

Purpose of the Study:

• To review the post-translational toolkit for mammalian synthetic biology.
• To highlight synthetic protein circuits utilizing proteolysis and phosphorylation.
• To discuss translating these circuits from tools to pre-clinical biomedical applications.

Main Methods:

• Review of literature on synthetic protein circuits.
• Emphasis on proteolysis and phosphorylation mechanisms.
• Analysis of native pathway rewiring versus orthogonal behavior creation.

Main Results:

• Synthetic protein circuits offer robust, rapid, and compact designs for cellular engineering.
• These circuits leverage programmable binding, proteolysis, or phosphorylation.
• Key differences between rewiring native pathways and creating orthogonal behaviors were identified.

Conclusions:

• Synthetic protein circuits represent a powerful toolkit for mammalian synthetic biology.
• These circuits have significant potential for gene therapies and pre-clinical biomedical applications.
• A framework for translating synthetic protein circuits into clinical use is proposed.