Immunoglobulin-Directed Phase Separation for Cell-Specific Modulation of Receptor Signaling
Weishuai Ren1, Peiyuan Zheng1, Ziting Zhou1
1School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China.
Insights
Researchers engineered a novel phase separation system using antibody-peptide interactions. This system specifically targets cancer cells, inducing apoptosis and inhibiting tumor growth for potential therapeutic applications.
Area of Science:
- Cellular Biology
- Biochemistry
- Immunology
Background:
- Liquid-liquid phase separation is crucial for cellular functions and signaling pathway modulation.
- Membrane-associated signaling complexes rely on phase separation for spatiotemporal control.
Purpose of the Study:
- To engineer a novel phase separation system for targeted cellular signaling modulation.
- To investigate the therapeutic potential of an immunoglobulin-directed phase separation system for cancer treatment.
Main Methods:
- Engineered a phase separation system using a mutant Fc fragment (human IgG1) and a specific peptide.
- Tethered phase separation scaffolds to nanobodies targeting CXCR4 and DR5 cell-surface receptors.
- Evaluated the system's efficacy in activating DR5 signaling and inducing tumor cell apoptosis in a xenograft model.
Main Results:
- Successfully engineered a phase separation system based on antibody-peptide multivalent interactions.
- Achieved specific activation of DR5 signaling in CXCR4+ cells.
- Demonstrated efficient tumor cell apoptosis and inhibition of tumor growth in vivo.
Conclusions:
- Immunoglobulin-directed phase separation systems offer a novel strategy for cell-specific signaling modulation.
- This engineered system shows potential for scientific research and therapeutic applications in cancer therapy.
- Phase separation systems can be utilized for targeted apoptosis induction and tumor growth inhibition.
Abstract:
Liquid-liquid phase separation is a fundamental process in cellular biology, influencing various cellular functions. Recent research highlights the critical role of phase separation in membrane-associated signaling complexes, where it spatiotemporally modulates signaling pathways. In this research, we have engineered a phase-separation system utilizing specific antibody-peptide multivalent interaction. In particular, the phase-separation system was constituted by a mutant Fc fragment from the human IgG1 and a peptide specifically bound to the mutant Fc. Further, by tethering the phase separation scaffolds to nanobodies targeting specific cell-surface receptors CXCR4 and DR5, we could specifically activate DR5 signaling in CXCR4+ cells. Moreover, the CXCR4/DR5-targeting phase separation system efficiently induced tumor cell apoptosis and tumor growth inhibition in the xenograft model, offering a novel strategy for tumor-specific apoptosis induction. This work demonstrates the potential of the immunoglobulin-directed phase separation systems as a tool for cell-specific signaling modulation for scientific research and therapeutic applications.
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