The early stages of the intracellular transport of membrane proteins: clinical and pharmacological implications

Intracellular transport mechanisms ensure that integral membrane proteins are delivered to their correct subcellular compartments. Efficient intracellular transport is a prerequisite for the establishment of both cell architecture and function. In the past decade, transport processes of proteins have also drawn the attention of clinicians and pharmacologists since many diseases have been shown to be caused by transport-deficient proteins. Membrane proteins residing within the plasma membrane are transported via the secretory (exocytotic) pathway. The general transport routes of the secretory pathway are well established. The transport of membrane proteins starts with their integration into the ER membrane. The ribosomes synthesizing membrane proteins are targeted to the ER membrane, and the nascent chains are co-translationally integrated into the bilayer, i.e., they are inserted while their synthesis is in progress. During ER insertion, the orientation (topology) of the proteins in the membrane is determined. Proteins are folded, and their folding state is checked by a quality control system that allows only correctly folded forms to leave the ER. Misfolded or incompletely folded forms are retained, transported back to the cytosol and finally subjected to proteolysis. Correctly folded proteins are transported in the membranes of vesicles through the ER/Golgi intermediate compartment (ERGIC) and the individual compartments of the Golgi apparatus (cis, medial, trans) to the plasma membrane. In this review, the current knowledge of the first stages of the intracellular trafficking of membrane proteins will be summarized. This early secretory pathway includes the processes of ER insertion, topology determination, folding, quality control and the transport to the Golgi apparatus. Mutations in the genes of membrane proteins frequently lead to misfolded forms that are recognized and retained by the quality control system. Such mutations may cause inherited diseases like cystic fibrosis or retinitis pigmentosa. In the second part of this review, the clinical implications of the early secretory pathway will be discussed. Finally, new pharmacological strategies to rescue misfolded and transport-defective membrane proteins will be outlined.Abbreviations AP1 Clathrin-associated adaptor protein complex 1 - AQP Aquaporin - ARF ADP-ribosylation factor - AVP 8-Arginine-vasopressin;BiP immunoglobulin heavy chain binding protein - CFTR Cystic fibrosis transmembrane conductance regulator - CLQTS Congenital long QT syndrome - CMT Charcot-Marie-Tooth syndrome - CNX Calnexin - COPI Coat protein complex I - COPII Coat protein complex II - CPX 8-Cyclopentyl-1,2-dipropylxanthine - CRT Calreticulin - CSID Congenital sucrose-isomaltase deficiency - Cx Connexin - cGMP Cyclic 3:5 guanosine monophosphate - ECL Extracellular loop - EndoH Endoglycosidase H - ER Endoplasmic reticulum - ERAD ER-associated degradation - ERGIC ER/Golgi intermediate compartment - ERp ER protein - ET_BR Human endothelin B receptor - FH Familial hypercholesterolemia - GABA Gamma amino butyric acid - GFP Green fluorescent protein - GH Growth hormone - GHIS Growth hormone insensitivity syndrome - GLCase Glucosidase - GlcNac N-acetylglucosamine - GPCR G protein-coupled receptor - GPI Glycosylphosphatidylinositol - G protein GTP-binding protein - GRP Glucose-regulated protein - HA Hemagglutinin - Hdj-2 Human DnaJ-2 protein - HFE Human hemochromatosis protein - HH Hereditary hemochromatosis - HEK 293 cells Human embryonic kidney 293 cells - HERG Human ether-a-go-go-related protein - Hsc70 Heat shock cognate 70 protein - ICL Intracellular loop - IGF-I Insulin-like growth factor-1 - I_Kr Rapidly activating delayed rectifier potassium current - I_Ks Slowly activating delayed rectifier potassium current - JAK Janus kinase - LDL Low-density lipoprotein - LH Luteinizing hormone/choriogonadotropin - LS Laron syndrome - MATP Membrane associated transporter protein - MDCK cells Madin-Darby canine kidney epithelial cells - MHC Major histocompatibility complex - MiRP1 minK-related peptide 1 - NDI Congenital nephrogenic diabetes insipidus - NMDA N-methyl-d-aspartate - OCA Oculocutaneous albinism - PDI Protein disulfide isomerase - Pgp P-glycoprotein - PKA Protein kinase A - PLP Proteolipid protein - PMP22 Peripheral myelin protein 22 - RP Primary retinitis pigmentosa - SI Sucrase-isomaltase - SNARE Ethylmaleimide-sensitive factor attachment protein - SRP Signal recognition particle - TCR T-cell antigen receptor - TM Transmembrane domain - TRAM Translocating chain-associated membrane protein - Tyr Tyrosinase - Tyrp1 Tyrosinase-related protein-1 - UGGT UDP-glucose:glycoprotein glucosyltransferase - VIP Vesicular-integral membrane protein - V₂R Vasopressin V₂ receptor - VSV Vesicular stomatitis virus