Scientists can control when and where specific cellular proteins are activated by using optogenetic tools – genetically encoded, engineered molecules that are embedded in cells and can be remotely controlled by external light. However, existing optogenetic tools for regulating covalent bond formation between proteins and cleavage of the polypeptide chain are often unstable, exhibit background activity in the dark, and may function poorly in complex cellular environments.

In research published online on September 11 in Nature Communications, Vladislav Verkhusha, Ph.D., Daria Shcherbakova, Ph.D., Mikhail Baloban, Ph.D., and colleagues have developed a next-generation optogenetic system that directly addresses the limitations of existing tools. Their innovation, called a photoswitchable intein (PS Intein), integrates inteins – protein segments found in bacteria, fungi, and some plants –  with a light-sensitive switch. When exposed to light, the PS Intein can trigger proteins to join together, separate, or be released, allowing scientists to control protein activity with pinpoint accuracy. Importantly, the system functions across many different proteins and cellular contexts. The team further demonstrated that PS Intein activity can also be guided by cell-specific signals, such as promoters active only in cancer or tumor-related cells, ensuring that only diseased cells are targeted while sparing healthy tissue. Moreover, the PS Intein-based light-controlled gene expression platform enables signal amplification, producing one of the highest light-inducible responses yet observed among similar optogenetic tools. This new technology has the potential to clarify how protein interaction networks orchestrate cell behavior and to enable safer, more precise therapies – for example, activating cancer-fighting proteins only within diseased tissues and only at the intended time.

Dr. Verkhusha is a professor of genetics, director of the Fluorescent Protein Resource Center, co-director of the Gruss Lipper Biophotonics Center at Einstein, and a member of the National Cancer Institute-designated Montefiore Einstein Comprehensive Cancer Center. Drs. Baloban and Shcherbakova are both research assistant professors of genetics at Einstein.