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Invited Review Prohormone and Proneuropeptide Synthesis and Secretion

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Invited Review Prohormone and Proneuropeptide Synthesis and Secretion Histology and Histol Histopathol (1997) 12: 1179-1188 Histopathology 001: 10.14670/HH-12.1179 From Cell Biology to Tissue Engineering http://www.hh.um.es Invited Review Prohormone and proneuropeptide synthesis and secretion M.J. Perone and M.G. Castro Molecular Medicine Unit, Department of Medicine, University of Manchester, Manchester, UK Summary. Hormones and neuropeptides in eukaryotic sorting mechanisms which separate proteins destined for cells, are synthesised as large precursor molecules in the the regulated or constitutive secretory pathways from rough endoplasmic reticulum (RER), from where they proteins destined to Iysosomes, mitochondria or plasma are translocated to the Golgi apparatus. The sorting of membrane. How are proteins targeted to specific proteins destined for the regulated secretory pathway organelles or compartments within eukaryotic cells? from those which will be released constitutively takes This can sometimes be explained because particular place in the trans-Golgi network (TGN). In both these amino acid sequences (sorting domains) within proteins pathways, vesicles need to be transported to the plasma can convey the capacity to recognise and interact with a membrane before their contents can be released by specific transporter/carrier protein which can in turn exocytosis. target the protein in question to its cellular destination. Hormones and neuropeptides need to be secreted However, in most cases, these transporter/carrier systems from the cells in which are synthesised to exert their or defined sorting domains have not been identified, biological actions, although they can also play paracrine therefore, other intracellular mechanisms must be and autocrine actions. Prohormones and proneuro­ postulated. peptides must undergo post-translational modifications Neuronal and endocrine tissues are constituted by which occur in determined subcellular compartments highly specialised secretory cells, which synthesise and within eukaryotic cells and are carried out in a strict release hormones and neuropeptides in a regulated succession of intracellular events, which give rise to fashion. Thus, the correct trafficking and sorting of biologically active products. hormones/neuropeptides within the secretory pathway of The biosynthesis of prohormones/proneuropeptides is these cells have profound physiological implications, not mediated by the action of endoproteolytic enzymes and only for single cell physiology, but also for the other post-translational modifying enzymes within the integration of crucial physiological responses within secretory pathway. The major focus of this review will higher organisms. Functions such as reproduction, be the biosynthetic pathway, sorting and intracellular response to stress, food intake, immune response, onset trafficking of prohormone and proneuropeptide of labour are all mediated by these peptide messengers. precursors within the secretory pathway of eukaryotic We will review published evidence which relates to cells. biosynthesis, intracellular sorting and trafficking of prohormones/proneuropeptides within the regulated and Key words: Prohormone, Proneuropeptide, Sorting, constitutive secretory pathways of neuronal and Trafficking, Secretory pathway, Post-translational endocrine cells. We will also discuss evidence from processing work done in our laboratory and work done by other groups which suggests, contrary to what was believed until recently, that biosynthesis, trafficking and sorting Introduction events affecting prohormones/proneuropeptides are not only dependent on their particular amino acid sequences, Eukaryotic cells possess an efficient biochemical but also determined by cell-type specific factors which at machinery for protein synthesis and secretion. present are unknown. Membrane surrounded compartments within these cells, allow a fine regulation of metabolic reactions such as 1. Prohormonelproneuropeptide processing: its role in hormone stability, biological activity and sorting Offprint requests to: Dr. Maria G. Castro, Molecular Medicine Unit, mechanisms Department of Medicine, University of Manchester, Stopford Bldg., Rm 1.302, Manchester M13 9PT, UK It has been previously demonstrated that hormones 1180 Biosynthesis of prohormones and neuropeptides are synthesised as precursor proteins, Cleavage at single basic amino acid residues may also e.g., prohormones and proneuropeptides. Until recently, occur, e.g., the endoproteolytic cleavage of rat it was believed that higher molecular weight protein prodynorphin by the prohormone convertase I (PC I) to precursors were not biologically active. Work done in yield an 8 leD prodynorphin derived-product and the C­ our laboratory has shown that the full length precursor peptide (Dupuy et aI., 1994). Although, the presence of for corticotrophin-releasing hormone (CRH) is basic amino acids is essential to confer an aqueous biologically active, i.e., it elicits the release of adreno­ environment at the site of cleavage, the secondary corticotrophin (ACTH) from primary cultures of rat structure of the surrounding amino acids also seems to anterior pituitary cells (Morrison et aI., 1995) and it play an important role (Rholam et aI., 1986). To date, induces cell proliferation of AtT20 cells, a corticotrophic several endoproteases involved in the endoproteolytic tumour cell line (Castro et aI., 1995b). Biologically processing of prohormones/proneuropeptides have been active peptides are released from their precursor proteins identified and cloned, and are known as precursor by enzymatic endoproteolytic cleavages. Most pro­ converting enzymes (PCEs) (for review see Smeekens, hormones/proneuropeptides contain within their amino 1993). These belong to the family of subtilisin/Kex2- acid sequence, peptides with different biological serine proteases and exhibit similar amino acid activities. Proopiomelanocortin (POMC) is endoproteo­ sequences at different domains such as furinIPACE, PCI, Iytically processed to yield ACTH, B-endorphin and u­ PC2, PACE4, PC4, PC5/PC6 and PC7. However, melanocyte stimulating hormone (Nakanishi et aI., differences have been attributed with respect proprotein 1979). Proenkephalin contains multiple copies of the specificity as well as tissue localisation for these same peptide, i.e., six copies of Met-enkephalin and one enzymes (Seidah et aI., 1994). An aspartyl endo­ copy of Leu-enkephalin (Comb et aI., 1982). The peptidase has been purified from bovine intermediate precursor of FMRF-amide synthesised by the neurons of lobe secretory vesicles, which possesses endoproteolytic the mollusc, Aplysia Cali/arnica contains this activity on POMC in vitro (Loh et aI., 1985); this tetrapeptide repeated 28 times within its amino acid enzyme cleaves mouse and toad POMC in vitro sequence and a single copy of the related peptide FLRF­ generating POMC-derived peptides found in the amide (Taussing and Scheller, 1986). intermediate lobe of the pituitary gland, in vivo (Castro Prohormones and proneuropeptides undergo several et aJ., 1989). modifications before they are released. These If cells need only one PCE or a particular modifications can be co-translational (i.e., removal of the combination of them to cleave a specific prohormonel signal peptide) or post-translational (after they are proneuropeptide still needs to be elucidated; altough the synthesised within the rough endoplasmic reticulum wide distribution of these enzymes in tissues of (RER)). Post-translational modifications are divided into neuronal/endocrine origin suggests that they might be two main categories: 1) proteolytic modifications which able to endoproteolytically process a wide number of involve endoproteases, carboxypeptidases and amino­ propeptides. The cellular machinery for endoproteolytic peptidases, and 2) chemical modifications done by processing and secretion has been conserved during enzymes which covalently modify the lateral chain of evolution, even in cells so evolutionary distant as yeast amino acids within peptides as: glycosylation, and neurons (Bennett and Scheller, 1993). This has been amidation, acetylation, phosphorylation and sulfation. demonstrated by Jung et aI., 1993, who showed that the Many of these enzymes have been biochemically endoproteolytic products of the egg-laying hormone characterised, localised to specific tissues or cellular (ELH) which is a prohormone synthesised within the bag compartments, and in most cases they have been cloned cell neurons of the marine mollusc, Aplysia califarnica, (Seidah et aI., 1990; Smeekens and Steiner 1990; Eipper are similar when this prohormone is expressed in AtT20 et aI., 1992). cells. The expression of heterologous proproteins within Endoproteolytic cleavages are one of the key steps in cells which do not possess a regulated secretory pathway the generation of many hormones/neuropeptides from and therefore do not synthesise the endoproteolytic their protein precursor molecules. After initial cleavage enzymes found in neuroendocrine cells such as PC 1 or of the signal peptide in the lumen of RER (Walter et aI., PC2, does not always yield endoproteolytically 1984) further proteolytic events of most prohormonesl processed products from the precursors, e.g., rat proneuropeptides start within late compartments of the proenkephalin (Lindberg et aI., 1991), mouse prorenin Golgi complex i.e., the trans Golgi network (TGN) (Hosaka et aJ., 1991) and rat procorticotrophin-releasing (Sossin et aI., 1990) and continue in the secretory hormone (proCRH) (Castro et aI., 1995b)
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