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RESEARCHERS FROM THE CENTRE FOR GENOMIC REGULATION (CRG) DESCRIBE A NEW SECRETORY PATHWAY FOR PROTEINS

The work which is published in the prestigious Journal of Cell Biology shows the mechanism of Acb1 secretion which is of fundamental interest for normal physiology and a variety of human pathologies.

Most secretory proteins released from the cells first enter the Endoplasmic Reticulum (ER) in a signal sequence dependent manner, following which, the signal sequence is cleaved and the protein is transported to the Golgi. After sorting in the Trans Golgi Network (TGN), the secretory proteins are packed into a special transport carrier, which fuse with the plasma membrane to release their content. This is the classical or the conventional pathway of protein secretion. However, a large number of proteins that lack a signal sequence for entering the ER are also secreted from the cells. The first report of this kind of unconventional secretion in 1990 was received poorly. How some proteins lacking a signal sequence are secreted remains poorly understood. The Intracellular Compartmentation laboratory leaded by Vivek Malhotra had reported previously that a Golgi associated protein, GRASP, was required for the unconventional secretion of a protein called ACBP in slime molds. In this new paper, the CRG researchers identify the path taken by the ACBP ortholog called Acb1 in yeast for secretion. Their findings reveal that Acb1 is captured into an autophagosome. Autophagosomes are membrane compartments that capture cytosolic material for degradation. However, unlike all other autophagosomes that fuse with the Vacuole thus degrading the contents, Acb1 containing autophagosomes are delivered to the cell surface. In other words, the Acb1 containing autophagosomes evade fusion with the vacuole. These autophagosomes fuse with an early endosomes thus generating a multivesicular body (MVB). MVB then fuses with the celll surface and releases Acb1. This paper reports the indentification of genes involved in this pathway of unconventional secretion. The protein called Acb1 that Juan Duran and Vivek Malhotra have found to be secreted unconventionally in yeast is also secreted by a number of mammalian cells. “Studying the role of GRASP and Acb1 sectretion in yeast allowed us to carry out a genetic analysis  indentifying and describing the pathway. Though yeast and human cells are different, the described mechanisms are highly preserved and they work in yeast and neurons as well” says Juan Duran. Acb1 is a protein linked to the normal cell function and some human pathologies. As an example, in the neurons this protein is known to be involved in controlling a number of neurological conditions such panic disorder, depression, addiction etc. In pancreas Acb1 is known to control high glucose dependent insulin secretion. So, understanding the mechanism of Acb1/DBI secretion and its mechanism of action is therefore of fundamental interest for normal physiology and a variety of human pathologies.Reference work: Duran, J.M., Anjard, C., Stefan, C, Loomis, W.F., and Malhotra, V. “Unconventional secretion of Acb1 is mediated by autophagosome”. Journal Cell Biology (2010). doi: 10.1083/jcb.2009.11.154 For further information: Laia Cendrós, Dept. Comunicació i RRPP, Centre de Regulació Genòmica (CRG), Dr. Aiguader, 88 – Edif. PRBB, 08003 Barcelona. Tel. +34 93 316 02 37.