Programmable On‐Chip Artificial Cell Producing Post‐Translationally Modified Ubiquitinated Protein

Abstract In nature, intracellular microcompartments have evolved to allow the simultaneous execution of tightly regulated complex processes within a controlled environment. This architecture serves as the blueprint for the construction of a wide array of artificial cells. However, such systems are inadequate in their ability to confine and sequentially control multiple central dogma activities (transcription, translation, and post‐translational modifications) resulting in a limited production of complex biomolecules. Here, an artificial cell‐on‐a‐chip comprising hierarchical compartments allowing the processing and transport of products from transcription, translation, and post‐translational modifications through connecting channels is designed and fabricated. This platform generates a tightly controlled system, yielding directly a purified modified protein, with the potential to produce proteoform of choice. Using this platform, the full ubiquitinated form of the Parkinson's disease‐associated α‐synuclein is generated starting from DNA, in a single device. By bringing together all central dogma activities in a single controllable platform, this approach will open up new possibilities for the synthesis of complex targets, will allow to decipher diverse molecular mechanisms in health and disease and to engineer protein‐based materials and pharmaceutical agents.