Room for Error in Secretory Pathways

In biological systems, the secretory pathway is a series of steps involved in secretion of a protein from a cell into the extracellular environment. It involves the journey of the protein that is destined to be secreted, from the ribosomes on the rough endoplasmic reticulum to the various compartments of the Golgi apparatus, packaged into a vesicle and finally secreted by exocytosis, via fusion with the plasma membrane. Each step in the pathway has factors determining the passage of the protein such as measures of transport regulation that signal protein location, the mechanics of proceeding further in the pathway, selection of proteins or modifications of the protein itself. Each of these factors contributes to the arrival and final structure of the secreted protein. In reference to error in the secretory pathway, there is extremely little room for any, as correct sorting and packaging is so crucial that mistakes lead to fatal and severe diseases. This essay will this outline the main stages of the secretory pathway, the levels of regulation and the consequences of error in the secretory pathway which will illustrate that there is minimal room for mistakes in this process.

Protein targeting or protein sorting is the mechanism by which cells transport proteins to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle, any of several interior membranes, the cell's outer membrane or its exterior via secretion. The delivery process is carried out based on information contained in the protein itself. This 'information' is coded as targeting signals which enable the cellular transport machinery to correctly position a protein inside or outside the cell. The information is contained in the polypeptide chain or in the folded protein. The continuous stretch of amino acid residues in the chain that enables targeting are called signal peptides. This short amino acid sequence functions as a postal code for the target organelle or location, and the synthesized protein can be transported either co-translationally or post-translationally, depending on the protein.

Proteins that are part of the secretory pathway are transported co-translationally which means that the proteins are translocated to the ER lumen as they are being synthesized, where they are glycosylated and where molecular chaperones aid proper folding. Soluble proteins in this class first are localized in the ER lumen and subsequently are sorted to the lumen of other organelles or are secreted from the cell. Likewise, the integral membrane proteins in this class initially are inserted into the rough ER membrane during their synthesis; some remain there, but many eventually become localized to the plasma membrane or membranes of the smooth ER, Golgi complex, lysosomes, or endosomes.

Most newly made proteins in the ER lumen or membrane are incorporated into small transport vesicles. These either fuse with the cis-Golgi or with each other to form the membrane stacks known as the cis-Golgi reticulum (network). From the cis-Golgi certain proteins, mainly ER-localized proteins, are retrieved to the ER via a different set of retrograde transport vesicles. In the process called cisternal migration, a new cis-Golgi stack with its cargo of luminal protein physically moves from the cis position (nearest the ER) to the trans position (farthest from the ER), successively becoming first a medial-Golgi cisterna and then a trans-Golgi cisterna. As this happens, membrane and luminal proteins are constantly being retrieved from later to earlier Golgi cisternae by small retrograde transport vesicles. By this process enzymes and other Golgi resident proteins come to be localized either in the cis- or medial- or trans-Golgi cisternae.

Proteins destined to be secreted move by cisternal migration to the trans face of the Golgi and then into a complex network of vesicles termed the trans-Golgi reticulum. From there a secretory protein is sorted into one of two types of vesicles, depending on the secretory pathway.

There are usually two types of secretory pathways- constitutive secretion and regulated secretion. In constitutive secretion, proteins are synthesised, packaged and secreted continuously notwithstanding environmental factors. Proteins are packaged in the Golgi bodies and secreted via exocytosis through the endomembrane pathway. No external signals are required for the process and cells that secrete constitutively have several scattered Golgi bodies in the cytosol. Some examples are collagen secretion by fibroblasts and secretion of serum proteins by hepatocytes. These proteins are sorted in the trans-Golgi network into transport vesicles that immediately move to and fuse with the plasma membrane, releasing their contents by exocytosis.

In other cells, the secretion of proteins is not continuous, but regulated, where the protein is packaged