CHAPTER 1 PART 4b

Current Research (Abstracts)

There are two schools of thought on this possibility. The first is thaat these proteins are attached to cytosolic organeles on their way to being phagocytosed, and as a result are delivered to the lysosome indirectly. The second possibility is that there could be a specific transport in the lysosome that recognizes this marker and transports this protein across the lysosomal membrane. It has been noted that there have been proteins that have been secreted from cells, such as basic fibroblast growth factor interleukin-1 which arrives at the cell surface without ever having entered the secretory pathway or passed through the ER and the golgi apparatus. In most cases it is not known which membrane the protein crosses or how the transmenbrane transport is catalyzed. We have been shown that a pheromone-a factor in yeast cells has been transported across the plasma membrane via an ATP-driven peptide pump. and there remains the possibility that a similar type pump could be responsible for transporting a small amount of proteins across a particular membrane. Lysosomal hydrolases and membrane proteins are synthesized in the rough ER and transported through the golgi apparatus. These vessicles which deliver these proteins to the late endosomes, and later form lysosomes are formed by the buds in the trans golgi network and incorporate lysosomal proteins while excluding others destined for other sites. The manner in whih this is done is that the lysosomal proteins carry a marker known as mannose-6 phosphate (M6P). This marker is added exclusively to the N-linked oligosaccharides of the soluble lysosomal enzymes, while they are in the lumen of the cis golgi network. The M6P is recognized by M6P receptor proteins or transmembrane proteins from the trans golgi network, and binds to the lysosomal hydrolases, packages them into particular transport vessicles that bud in the trans golgi network, then fuse them to the lumen of this organelle. This protein binds its oligosaccharide in the trans golgi network at a ph of 7, and releases it at a ph of 6 which is the same ph as the interior of the late endosomes. In the late endosomes the lysosomal hydrolases separate from the M6P recoptor and begin to digest the material from the early endosomes. After releasing their bound enzymes, they are retrieved to the vessicles derived from the buds in the late endosomes and are returned to the membrane of the trans golgi network. Not all of the matrerial bound for the lysosomes gets to its destination, but some escapes the normal packaging and wind up in a default pathway to the cell surface where they are secreted into a cellular fluid. Some of these receptors also take a detour to the plasma membrane where they help rectify the errors in the lysosomal hydrolase routing by capturing them through receptor-mediated endocytosis to the lysosomes. The scavenger pathway was found in the studies of humans with genetically defective lysosomal hydrolases. In these cases the enzyme responsible for the breakdown of glycosaminoglycans does not exist. This results in the accumulation of masses of undigested molecules, and therefore are regarded as lysosomal storage disease. Cells cultured from mutant individuals exhibit the same abnormality, but wheb they are co-cultured with normal cells discarding the lysosomal hyrolase into the media and the mutants picking it up from the media to correct their deficiency. © BOTRESEARCH USA 1998-2012