Regulation of Protein Secretion Through Controlled Aggregation in the Endoplasmic Reticulum

TLDR

A system was developed to directly control protein secretion pharmacologically, enabling rapid and pulsatile delivery of therapeutic proteins. An engineered protein that aggregates in the ER is disaggregated by a synthetic small‑molecule drug to trigger secretion. Rapid, transient secretion of growth hormone and insulin was achieved in vitro and in vivo, and a pulse of insulin transiently corrected serum glucose in a hyperglycemic mouse, suggesting this method could enable gene therapy for polypeptides requiring rapid, regulated delivery.

Abstract

A system for direct pharmacologic control of protein secretion was developed to allow rapid and pulsatile delivery of therapeutic proteins. A protein was engineered so that it accumulated as aggregates in the endoplasmic reticulum. Secretion was then stimulated by a synthetic small-molecule drug that induces protein disaggregation. Rapid and transient secretion of growth hormone and insulin was achieved in vitro and in vivo. A regulated pulse of insulin secretion resulted in a transient correction of serum glucose concentrations in a mouse model of hyperglycemia. This approach may make gene therapy a viable method for delivery of polypeptides that require rapid and regulated delivery.