The Mechanism of Unconventional Protein Secretion

A large number of important secreted proteins are exported from cells independent of the classical endoplasmic reticulum (ER)-Golgi complex pathway of secretion. Examples include the Diazepam binding inhibitor (also known as acyl CoA binding protein), inflammatory cytokine interleukin-1ß (IL-1ß), insulin degrading enzyme, fibroblast growth factors 1 and 2, and superoxide dismutase (SOD1)

How are these signal sequence lacking proteins exported from cells? Is there a common pathway of their export? Does their release from the cytoplasm to the extracellular space involve a membrane bounded vesicular intermediate or are they translocated directly from the cytoplasm to the extracellular space via a translocator?

Our lab has focused on the role of GRASP proteins in unconventional protein secretion. This process is conserved across eukaryotes, therefore we employ different model systems, from yeast to mice to understand the molecular mechanism of unconventional protein secretion.

In yeast, GRASP is required for starvation induced secretion of acyl CoA binding protein (Acb1) and localizes to a novel compartment we have called CUPS (compartment for unconventional protein secretion). We have identified other proteins following the same pathway, including superoxide dismutase (SOD1). SOD1 is implicated in both familiar and sporadic amyotrophic lateral sclerosis (ALS) and very little is known about the mechanism of how SOD1 leads to this neurodegenerative disorder.

More recently we have generated a mouse knock-out of GRASP55 and can show that macrophages isolated from these mice require GRASP to secrete IL-1ß; in response to stimulation. We are using biochemical, genetic, super resolution microscopy and mouse genetics techniques to reveal how cells secrete Acb1, SOD1 and IL-1ß. Our findings will have major impact in our overall understanding of this pathway of protein secretion and human pathologies such as inflammation and neuronal dysfunction.