Abstract: Provided herein is a fusion protein comprising: (a) an extracellular domain comprising a first binding moiety that is capable of specifically binding to a first cell surface marker: (b) a transmembrane domain: and (c) an intracellular domain comprising: i. a first dimerization domain that specifically binds to a corresponding target dimerization domain in a target protein: and ii. a degradation domain, wherein the degradation domain is a degron or E3 ligase-recruiting domain. Protein circuits. cells and methods that make use of the fusion protein are also provided.

Abstract: Provided herein are a variety of molecular feed-forward circuits. In some embodiments a molecular feed-forward circuit may comprise a first nucleic acid comprising a first nucleotide sequence encoding a regulatory protein that is activated by a first exogenous stimulus, and a second nucleic acid comprising a second nucleotide sequence encoding a signaling protein that is activated by the first exogenous stimulus, where the target protein has a regulatory motif and the activated regulatory protein inactivates the target protein via the regulatory motif. The molecular circuit can further comprise a controller protein that is activated by a second exogenous signal, wherein the controller protein controls the interaction between the regulatory protein and the target protein. In this circuit activation of the regulatory protein is delayed relative to the activation of the target protein. The system can be used to produce a pulse of signaling and/or a concentration filter, for example.

Abstract: Described herein is a therapeutic cell that expresses a fusion protein comprising: (a) a target-binding domain; and (b) a degradation domain, e.g., a degron or E3 ligase-recruiting domain, that is heterologous to the target-binding domain. In the therapeutic cell, binding of the fusion protein to a target protein via the target-binding domain induces degradation of the target protein. The therapeutic cell can be an immunostimulatory cell, an immunoinhibitory cell or a stem cell, for example. Methods of treatment using the cell are also provided.