Custom built transport carriers

Over the last 2 decades, as an independent investigator, my laboratory has addressed the mechanisms of cell compartmentation and the mechanisms of general-or the conventional-protein secretion. Our recent adventures have taken us into the poorly marked area of unconventional protein secretion. Eukaryotic cells utilize the endoplasmic reticulum (ER)-to-Golgi pathway for the secretion of the vast majority of secretory proteins. This process is initiated by signal peptide-dependent protein translocation into the lumen of the ER followed by vesicular transport of secretory cargo to the Golgi and thence the cell surface. However, a significant number of proteins lacking a signal peptide are secreted without entering the conventional pathway. Insulin is secreted by the conventional pathway and insulin degrading enzymes, unconventionally. It makes sense, no? The cells separate the substrate from its degrading enzyme prior to reaching the final destination. But how did we end up studying unconventional secretion? We were trying to find the function of a protein called GRASP which, based on in vitro data, had been assigned the role of stacking Golgi cisternae. The proposal didn’t make sense because yeast contain GRASP but do not stack Golgi cisternae and plants contain some of the best looking stacks of Golgi cisternae but are devoid of GRASP protein. We found GRASP was required for the secretion of a signal sequence lacking protein called Acb1 (Acyl-CoA binding protein). The secretion of Acb1 is mediated by an autophagosome like vesicles, which form at a new compartment called CUPS for Compartment for Unconventional Protein Secretion. We are now in a position to investigate this novel pathway of protein secretion. If time permits, I will also discuss how cells make mega carriers to pack large collagens for export from the ER. Put simply, cells use a variety of components to design transport carriers commensurate with the size and the properties of the cargo, and we would like to know how these decisions are made and executed.

Kinseth, M.A., C. Anjard, D. Fuller, G. Guizzunti, W.F. Loomis, and V. Malhotra. 2007. The Golgi-associated protein GRASP is required for unconventional protein secretion during development. Cell. 130:524-534.


Saito, K., Chen, M., Bard, F., Chen, S., Zhou, H., Woodley, D., Polischuk, R., Schekman, R., and Malhotra. V. TANGO1: a protein required for collagen VII packing into COPII transport carriers. Cell 136: 891-902 (2009).


Duran, J.M., C. Anjard, C. Stefan, W.F. Loomis, and V. Malhotra. 2010. Unconventional secretion of Acb1 is mediated by autophagosomes. J. Cell Biol. 188:527-536.


Bruns,C., J.M., McCaffery,A.J., Curwin, J.M., Duran, and V. Malhotra. 2011. Biogenesis of a novel compartment for autophagosome-mediated unconventional protein secretion. J.Cell.Biol.195:979-992.