Development and Recent Advances in SLIPT‐PM: A Chemogenetic Platform for Manipulating Signaling at the Plasma Membrane

Upon cell stimulation, mammalian cells activate various signaling proteins and lipids by recruiting their upstream regulators to the inner leaflet of the plasma membrane (PM), which in turn determines their cellular response. Therefore, artificially inducing protein translocation to the PM is an effective strategy for dissecting cell signaling networks and engineering cellular functions. Self-localizing ligand-induced protein translocation (SLIPT) is an emerging technique that we developed to control protein localization in living cells using synthetic self-localizing ligands (SLs). Building on this strategy, we recently introduced a versatile chemogenetic SLIPT platform that rapidly recruits proteins of interest fused to an engineered Escherichia coli dihydrofolate reductase tag from the cytoplasm to the PM using a trimethoprim-based SL. The PM-specific SLIPT (SLIPT-PM) system is easy to use and enables researchers to manipulate diverse intracellular signaling molecules and pathways with controlled reversibility and repeatability. Owing to its modular design, related SLIPT-PM tools have also been developed to support more sophisticated experiments, such as light-induced spatially regulated protein recruitment and multiplexed signal manipulation. In this concept article, we review the development, principal features, current applications, and future challenges of SLIPT-PM as a unique tool in chemical biology and synthetic biology.