ABSTRACT

S ecretion of proteins is an essential mechanism for life. Eukaryotic cells developed the complex central vacuolar system build up by the endoplasmic reticulum (ER), the Golgi apparatus, endosomes, lysosom es, the plasm a membrane and intermediate transport compartments to guarantee proper protein transport and sorting through the vacuolar system itself or the extracellular milieu.1,2 The ER is the site of entry of soluble and membrane proteins into this system. The proteins are inserted into the ER membrane or imported into the lumen in an unfolded state, accom panied by glycosylation, disulfide bridge formation and cleaving of signal sequences.3 An important function of the ER rests in the folding of nascent polypeptides into their native conformation, which finally enables them to take over their biological function after transport to their site of action.4 The ER lumen is extremely protein folding competent, since it contains a high concentration of molecular chaperones in a dense calcium/protein matrix.5 The presence of these chaperones establishes a highly efficient quality control system permitting the delivery of only properly folded proteins. After proofreading of the folding status of a protein, a decision is made on further transport to its site of action or to rapid

degradation. The molecular basis of the decision on protein life or death could be provided by the number of unsuccessful folding cycles of a given polypeptide chain. According to this model, the trimming of carbohydrate chains could establish the time frame available for protein folding.6 Although this is a fascinating idea, it remains unsolved what pulls the trigger for degradation of unglycosylated proteins, like a mutant version of the yeast a factor (see below).