Chemically Synthetic Membrane Receptors Establish Cells with Artificial Sense-and-Respond Signaling Pathways

Abstract

Chemically synthetic receptors that establish cells a new sense-and-respond capability to interact with outer worlds are highly desired, but rarely reported. In this work, we develop a membrane-anchored synthetic receptor (Ts-pHLIP-Pr) using DNA and peptide as the building block to equip cells with artificial signaling pathways. Upon sensing external pH stimuli, the Pr module can be translocated across the cell membrane via the conformation switch of pHLIP, enabling membrane-proximal recruitment of specific proteins to trigger downstream signaling cascades. Our experimental results demonstrate the capability of Ts-pHLIP-Pr for regulating PKCε-related signaling events upon responding to external pH reduction. With a modular feature, this receptor can be extended to elicit T cell activation through low-pH environment-induced directional movement of cytoplasmic ZAP70. Our work is expected to offer a new paradigm for intelligent synthetic biology and customized cell engineering.

Lipophilic Anchors that Embed Bioconjugates in Bilayer Membranes: A Review

“…It has performance advantages compared to pH-switchable transmembrane helical membrane peptides such as pHLIP or cell penetrating peptides. 80,81 Finally, a conceptually new way to reversibly anchor molecular payload in a PEG-coated membrane was reported based on the affinity of polycyclic aromatic hydrocarbons, such as pyrenyl, for a layer of PEG chains. 82 Upon mixing, pyrenyl conjugates with appended dyes and functional groups were rapidly embedded in the PEG corona surrounding nanoscale polymersomes.…”

“…The construct has promise as a light-switchable molecular probe to study the dynamic process of helical peptide insertion into membranes. It has performance advantages compared to pH-switchable transmembrane helical membrane peptides such as pHLIP or cell penetrating peptides. , …”

Functional Nucleic Acid-Based Immunomodulation for T Cell-Mediated Cancer Therapy

“…The functionalized cells could then specifically bind with target cells and induce cellular apoptosis. To translate extracellular recognition events into intracellular signaling cascades, Wu et al constructed synthetic membrane receptors (Ts-pHLIP-Pr) capable of detecting and responding to external stimuli . Upon sensing external pH reduction, Ts-pHLIP-Pr would undergo a conformational switch and enable its free end to translocate across the cell membrane.…”

“…To translate extracellular recognition events into intracellular signaling cascades, Wu et al constructed synthetic membrane receptors (Ts-pHLIP-Pr) capable of detecting and responding to external stimuli. 160 Upon sensing external pH reduction, Ts-pHLIP-Pr would undergo a conformational switch and enable its free end to translocate across the cell membrane. By incorporating a targeting module at the free end, this artificial receptor allowed recruitment of specific cytoplasmic proteins to the membraneproximal region and then regulated downstream signaling events (Figure 9b).…”

“…(b) Chemically synthetic membrane receptors established cells with artificial sense-and-respond signaling pathways. Reproduced with permission from ref . Copyright 2023 American Chemical Society.…”