Eukaryotic cells are divided into functionally different regions surrounded by membranes – compartments. Intracellular membranes encompass about half of the entire cell into these individual intracellular compartments.
The internal membranes of a eukaryotic cell make possible the functional specialization of various membranes, which is the decisive factor in the separation of many different processes occurring in the cell (1).Each newly synthesized protein of the cell organelles passes from the ribosome to the organelle in a special way, determined by either the signal peptide or signaling region. The process of protein sorting begins with primary segregation, in which the protein either remains in the cytosol, or is transferred to another compartment. Proteins entering the ER undergo further sorting as they are transferred to the Golgi apparatus and then from the Golgi apparatus to the lysosomes, into the secretory vesicles or to the plasma membrane.
Some proteins remain in the ER and various cisterns of the Golgi apparatus. Proteins destined for other compartments, get inside the transport vesicles that then detach from one compartment and merge with another (1).In the ER, the presence of the KDEL signal sequence (Lys-Asp-Glu-Leu) at the C-termini of resident proteins serves as a signal for initiation of the process separating resident proteins of this organelle (selection proteins) from all other transit proteins. The “catching” of proteins of the endoplasmic reticulum occurs in apparatus Golgi, where there is a receptor for KDEL. Then the proteins in the complex with the receptor return to the endoplasmic reticulum by retrograde transport.
UV-induced random mutagenesis allowed scientists to obtain two yeast mutations – in ERD1 and ERD2 – with impaired capacity to retain resident proteins endoplasmic reticulum in the cells. Products of these genes were localized in cis-Golgi and in medial Golgi respectively. Mutation in the ERD1 is pleiotropic (has more than just one effect): yeast cells that have a defect in this gene also have impairments in processes like N-glycosylation and O-glycosylation as well as in transportation of proteins in the vacuole (2).ER-associated degradation (ERAD) is the process occurring in the cell that allows to prevent improperly assembled proteins from premature egress, and to destroy terminally misfolded proteins. ERAD helps to assure that defective proteins leave the cell without affecting normal protein functioning. Studies suggest that the improper presentation of sorting signals and retrieval from post-ER compartments contribute to ER retention of misfolded proteins. Accumulation of misfolded proteins in the ER triggers a transcriptional pathway UPR – the unfolded protein response that upregulates both ER chaperones and the degradation machinery. ERAD and UPR provide ER homeostasis; when ERD2-mediated retrieval is impaired, the UPR compensate maintenance of viability by increasing the levels of ER chaperones (3).
Mislocalized proteins can result in different pathologies, and protein AVPR2 is one of the examples. Normally, excessive loss of water through urination is prevented by the release of the hormone arginine-vasopressin (AVP) from the posterior pituitary. Binding of AVP to its type-2 receptor (AVPR2) triggers the exocytosis of the water channel aquaporin 2 (AQP2) at the apical membrane the principal cells of the collecting duct. ER retention of AVPR2 results in a mutation leading to nephrogenic diabetes insipidus. This disease is characterized by the lack of responsiveness of the collecting duct to the antidiuretic action of the hormone AVP.
People with nephrogenic diabetes insipidus due to their inability to concentrate the urine, have polyuria and compensatory polydipsia, therefore are at risk of severe dehydration. Currently there is no cure for nephrogenic diabetes insipidus, its symptomatic treatment is based on a continuous supply of water, restrictive diet, and nonspecific drugs.