RNA-Guided Control Of Protein Secretion And Membrane Protein Expression

Published: September 26, 2024

Lead Inventor: Chuan He

The Unmet Need: Non-protein agents to engineer the secretory pathway to boost biotherapeutic protein production

Protein secretion is a fundamental biological process with significant implications for human health and disease. It plays a crucial role in various physiological functions, including cell signaling, immune response, and the production of hormones and enzymes. The ability to control and enhance protein secretion has immense potential in developing novel therapeutics and improving biopharmaceutical production. For instance, many biotherapeutic proteins, such as insulin and growth hormones, are produced through recombinant DNA technology and require efficient secretion from the host cells for therapeutic efficacy.
Current approaches for enhancing protein secretion often rely on empirical strategies, such as optimizing cell culture conditions, engineering signal peptides, or overexpressing chaperone proteins. These methods, while effective to some extent, often lack specificity and can have unpredictable effects on cellular physiology. For example, overexpressing chaperone proteins may lead to the accumulation of misfolded proteins, triggering cellular stress responses and impacting overall cellular health. Additionally, these approaches often fail to address the complexity of the secretory pathway, which involves a highly coordinated network of proteins and RNA molecules.

The faculty inventor developed methods to utilize small nucleolar RNAs (snoRNAs) to regulate protein secretion and membrane protein expression by targeting messenger RNAs (mRNAs) through base pairing. While protein secretion is typically controlled by N-terminal signal peptides, this method leverages snoRNAs as non-protein signals. These snoRNAs enhance protein secretion by interacting with both mRNAs and 7SL RNA, a crucial component of the signal recognition particle (SRP) responsible for protein delivery to the endoplasmic reticulum (ER). This interaction strengthens the association between the translation machinery and SRP, thereby boosting secretion efficiency.
snoRNA-guided protein secretion offers a more targeted and versatile approach. By engineering specific snoRNA binding sequences, it becomes possible to modulate the secretion of specific proteins with high precision. This method holds immense potential for various applications, including disease treatment and biotherapeutic production, by enabling fine-tuned control over protein secretion in both in vivo and in vitro settings.