BBA - Molecular Cell Research (v.1833, #11)
Editorial Board (i).
From rags to riches — The history of the endoplasmic reticulum by Maya Schuldiner; Blanche Schwappach (2389-2391).
Co-translational targeting and translocation of proteins to the endoplasmic reticulum by Yvonne Nyathi; Barrie M. Wilkinson; Martin R. Pool (2392-2402).
Co-translational protein targeting to the endoplasmic reticulum (ER), represents an evolutionary-conserved mechanism to target proteins into the secretory pathway. In this targeting pathway proteins possessing signal sequences are recognised at the ribosome by the signal recognition particle while they are still undergoing synthesis. This triggers their delivery to the ER protein translocation channel, where they are directly translocated into the ER. Here we review the current understanding of this translocation pathway and how molecular details obtained in the related bacterial system have provided insight into the mechanism of targeting and translocation. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► SRP is able to detect signal sequences as they emerge from the ribosome. ► SRP retards translation to create a time window for ER targeting. ► SRP receptor transfers the ribosome nascent chain complex from SRP to the translocon. ► The Sec61 channel conveys the nascent chain from the ribosome directly into the ER lumen. ► Sec61 can also insert membrane proteins into the lipid bilayer.
Keywords: Protein translocation; Protein targeting; Protein biogenesis; Ribosome; Signal recognition particle; Translocon;
Post-translational translocation into the endoplasmic reticulum by Nicholas Johnson; Katie Powis; Stephen High (2403-2409).
Proteins destined for the endomembrane system of eukaryotic cells are typically translocated into or across the membrane of the endoplasmic reticulum and this process is normally closely coupled to protein synthesis. However, it is becoming increasingly apparent that a significant proportion of proteins are targeted to and inserted into the ER membrane post-translationally, that is after their synthesis is complete. These proteins must be efficiently captured and delivered to the target membrane, and indeed a failure to do so may even disrupt proteostasis resulting in cellular dysfunction and disease. In this review, we discuss the mechanisms by which various protein precursors can be targeted to the ER and either inserted into or translocated across the membrane post-translationally. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► Many proteins are post-translationally delivered to the endoplasmic reticulum. ► Multiple cytoplasmic components and molecular chaperones including TRC40/GET pathway components facilitate their delivery. ► Short secretory proteins are post-translationally translocated across the Sec61 translocon. ► The membrane integration step for tail-anchored proteins is undefined.
Keywords: Asna 1; Get3; TRC40; Tail-anchored protein; Short secretory protein;
Orchestration of secretory protein folding by ER chaperones by Tali Gidalevitz; Fred Stevens; Yair Argon (2410-2424).
The endoplasmic reticulum is a major compartment of protein biogenesis in the cell, dedicated to production of secretory, membrane and organelle proteins. The secretome has distinct structural and post-translational characteristics, since folding in the ER occurs in an environment that is distinct in terms of its ionic composition, dynamics and requirements for quality control. The folding machinery in the ER therefore includes chaperones and folding enzymes that introduce, monitor and react to disulfide bonds, glycans, and fluctuations of luminal calcium. We describe the major chaperone networks in the lumen and discuss how they have distinct modes of operation that enable cells to accomplish highly efficient production of the secretome. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Endoplasmic reticulum; Chaperones; Protein folding; Secretome;
Forming disulfides in the endoplasmic reticulum by Ojore B.V. Oka; Neil J. Bulleid (2425-2429).
Protein disulfide bonds are an important co- and post-translational modification for proteins entering the secretory pathway. They are covalent interactions between two cysteine residues which support structural stability and promote the assembly of multi-protein complexes. In the mammalian endoplasmic reticulum (ER), disulfide bond formation is achieved by the combined action of two types of enzyme: one capable of forming disulfides de novo and another able to introduce these disulfides into substrates. The initial process of introducing disulfides into substrate proteins is catalyzed by the protein disulfide isomerase (PDI) oxidoreductases which become reduced and, therefore, have to be re-oxidized to allow for further rounds of disulfide exchange. This review will discuss the various pathways operating in the ER that facilitate oxidation of the PDI oxidoreductases and ultimately catalyze disulfide bond formation in substrate proteins. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► Disulfide formation in the ER is an enzyme catalyzed process. ► The process requires a disulfide exchange protein and an oxidase. ► PDI proteins are the main disulfide exchange proteins in the ER. ► Ero1, PrxIV, GPx 7/8, VKOR can all act as PDI oxidases. ► The correct ER redox conditions are required for native disulfide formation.
Keywords: Disulfide bond; Thiol-disulfide exchange; Protein disulfide isomerase (PDI); Oxidoreductase; Peroxidase; Sulfenylation;
N-linked protein glycosylation in the ER by Markus Aebi (2430-2437).
N-linked protein glycosylation in the endoplasmic reticulum (ER) is a conserved two phase process in eukaryotic cells. It involves the assembly of an oligosaccharide on a lipid carrier, dolichylpyrophosphate and the transfer of the oligosaccharide to selected asparagine residues of polypeptides that have entered the lumen of the ER. The assembly of the oligosaccharide (LLO) takes place at the ER membrane and requires the activity of several specific glycosyltransferases. The biosynthesis of the LLO initiates at the cytoplasmic side of the ER membrane and terminates in the lumen where oligosaccharyltransferase (OST) selects N-X-S/T sequons of polypeptide and generates the N-glycosidic linkage between the side chain amide of asparagine and the oligosaccharide. The N-glycosylation pathway in the ER modifies a multitude of proteins at one or more asparagine residues with a unique carbohydrate structure that is used as a signalling molecule in their folding pathway. In a later stage of glycoprotein processing, the same systemic modification is used in the Golgi compartment, but in this process, remodelling of the N-linked glycans in a protein-, cell-type and species specific manner generates the high structural diversity of N-linked glycans observed in eukaryotic organisms. This article summarizes the current knowledge of the N-glycosylation pathway in the ER that results in the covalent attachment of an oligosaccharide to asparagine residues of polypeptide chains and focuses on the model organism Saccharomyces cerevisiae. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Glycosylation; Oligosaccharyltransferase;
Protein O-mannosylation: What we have learned from baker's yeast by Martin Loibl; Sabine Strahl (2438-2446).
Background: Protein O-mannosylation is a vital type of glycosylation that is conserved among fungi, animals, and humans. It is initiated in the endoplasmic reticulum (ER) where the synthesis of the mannosyl donor substrate and the mannosyltransfer to proteins take place. O-mannosylation defects interfere with cell wall integrity and ER homeostasis in yeast, and define a pathomechanism of severe neuromuscular diseases in humans. Scope of review: On the molecular level, the O-mannosylation pathway and the function of O-mannosyl glycans have been characterized best in the eukaryotic model yeast Saccharomyces cerevisiae. In this review we summarize general features of protein O-mannosylation, including biosynthesis of the mannosyl donor, characteristics of acceptor substrates, and the protein O-mannosyltransferase machinery in the yeast ER. Further, we discuss the role of O-mannosyl glycans and address the question why protein O-mannosylation is essential for viability of yeast cells. General significance: Understanding of the molecular mechanisms of protein O-mannosylation in yeast could lead to the development of novel antifungal drugs. In addition, transfer of the knowledge from yeast to mammals could help to develop diagnostic and therapeutic approaches in the frame of neuromuscular diseases. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► Protein O-mannosylation is a vital modification that is conserved among fungi and animals. ► O-mannosylation is initiated in the endoplasmic reticulum (ER) by the PMT family of mannosyltransferases. ► Protein O-mannosyltransferases show specificity towards their protein substrates. ► O-mannosylation defects interfere with ER homeostasis and cell wall integrity in yeast. ► In baker's yeast, protein O-mannosylation and N-glycosylation are interdependent.
Keywords: Cell wall; Endoplasmic reticulum; Glycosylation; Protein O-mannosylation; PMT; Unfolded protein response;
How early studies on secreted and membrane protein quality control gave rise to the ER associated degradation (ERAD) pathway: The early history of ERAD by Patrick G. Needham; Jeffrey L. Brodsky (2447-2457).
All newly synthesized proteins are subject to quality control check-points, which prevent aberrant polypeptides from harming the cell. For proteins that ultimately reside in the cytoplasm, components that also reside in the cytoplasm were known for many years to mediate quality control. Early biochemical and genetic data indicated that misfolded proteins were selected by molecular chaperones and then targeted to the proteasome (in eukaryotes) or to proteasome-like particles (in bacteria) for degradation. What was less clear was how secreted and integral membrane proteins, which in eukaryotes enter the endoplasmic reticulum (ER), were subject to quality control decisions. In this review, we highlight early studies that ultimately led to the discovery that secreted and integral membrane proteins also utilize several components that constitute the cytoplasmic quality control machinery. This component of the cellular quality control pathway is known as ER associated degradation, or ERAD. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Endoplasmic reticulum; Molecular chaperone; Proteasome; Ubiquitin; Lysosome; ERAD;
Evolution of the unfolded protein response by Julie Hollien (2458-2463).
The unfolded protein response (UPR) is a network of signaling pathways that responds to stress in the endoplasmic reticulum (ER). The general output of the UPR is to upregulate genes involved in ER function, thus restoring and/or increasing the capacity of the ER to fold and process proteins. In parallel, many organisms have mechanisms for limiting the load on the ER by attenuating translation or degrading ER-targeted mRNAs. Despite broad conservation of these signaling pathways across eukaryotes, interesting variations demonstrate a variety of mechanisms for managing ER stress. How do early-diverging protozoa respond to stress when they lack traditional transcriptional regulation? What is the role of the ER stress sensor Ire1 in fungal species that are missing its main target? Here I describe how diverse species have optimized the UPR to fit their needs. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► The UPR is an ancient network of pathways that responds to ER stress. ► Protozoa respond to ER stress through regulation of translation and mRNA stability. ► Plants rely largely on transcriptional responses to ER stress. ► The UPR in plants, as in animals, is important for secretory cell function. ► Studies in fungi suggest an alternative ancestral function for Ire1.
Keywords: ER stress; Protein secretion; Ire1; Perk; Atf6;
Vesicle-mediated export from the ER: COPII coat function and regulation by Jennifer G. D'Arcangelo; Kyle R. Stahmer; Elizabeth A. Miller (2464-2472).
Vesicle trafficking from the endoplasmic reticulum (ER) is a vital cellular process in all eukaryotes responsible for moving secretory cargoes from the ER to the Golgi apparatus. To accomplish this feat, the cell employs a set of conserved cytoplasmic coat proteins – the coat protein II (COPII) complex – that recruit cargo into nascent buds and deform the ER membrane to drive vesicle formation. While our understanding of COPII coat mechanics has developed substantially since its discovery, we have only recently begun to appreciate the factors that regulate this complex and, in turn, ER-to-Golgi trafficking. Here, we describe these factors and their influences on COPII vesicle formation. Properties intrinsic to the GTP cycle of the coat, as well as coat structure, have critical implications for COPII vesicle trafficking. Extrinsic factors in the cytosol can modulate COPII activity through direct interaction with the coat or with scaffolding components, or by changing composition of the ER membrane. Further, lumenal and membrane-bound cargoes and cargo receptors can influence COPII-mediated trafficking in equally profound ways. Together, these factors work in concert to ensure proper cargo movement in this first step of the secretory pathway. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► COPII mediated secretion may be more intricately regulated than was initially appreciated. ► Cytosolic components regulate COPII vesicle formation through interactions with scaffolding proteins and the ER membrane. ► Cargo and cargo receptors influence vesicle formation by the membrane properties they impart at ER exit sites. ► Post-translational modifications may influence protein–protein interactions between coat components.
Keywords: COPII; Vesicle; Endoplasmic reticulum; Cargo export; Cargo receptor;
Transport of glycosylphosphatidylinositol-anchored proteins from the endoplasmic reticulum by Taroh Kinoshita; Yusuke Maeda; Morihisa Fujita (2473-2478).
In this review on the transport of glycosylphosphatidylinositol-anchored proteins (GPI-APs), we focus on events that occur in the endoplasmic reticulum after the transfer of GPI to proteins. These events include structural remodeling of both the lipid and glycan moieties of GPI, recruitment of GPI-APs into ER exit sites, association with the cargo receptor, p24 protein complex, and packaging into COPII coated transport vesicles. Similarities with the transport of Wnt proteins are also discussed. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► After attachment to proteins both lipid and glycan of GPI anchors are remodeled. ► Remodeling of GPI is required for efficient sorting into ERES and COPII coated vesicles. ► A complex of p24 family proteins acts as a cargo receptor for GPI-AP. ► GPI-AP and Wnt proteins are lipid-modified and transported similarly from the ER.
Keywords: Cargo receptor; COPII coated vesicles; Endoplasmic reticulum exit site; Glycosylphosphatidylinositol; Wnt;
A molecular ensemble in the rER for procollagen maturation by Yoshihiro Ishikawa; Hans Peter Bächinger (2479-2491).
Extracellular matrix (ECM) proteins create structural frameworks in tissues such as bone, skin, tendon and cartilage etc. These connective tissues play important roles in the development and homeostasis of organs. Collagen is the most abundant ECM protein and represents one third of all proteins in humans. The biosynthesis of ECM proteins occurs in the rough endoplasmic reticulum (rER). This review describes the current understanding of the biosynthesis and folding of procollagens, which are the precursor molecules of collagens, in the rER. Multiple folding enzymes and molecular chaperones are required for procollagen to establish specific posttranslational modifications, and facilitate folding and transport to the cell surface. Thus, this molecular ensemble in the rER contributes to ECM maturation and to the development and homeostasis of tissues. Mutations in this ensemble are likely candidates for connective tissue disorders. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Collagen; Endoplasmic reticulum; Biosynthesis; Posttranslational modification; Molecular chaperone; Extracellular matrix;
Untangling the web: Mechanisms underlying ER network formation by Uma Goyal; Craig Blackstone (2492-2498).
The ER is a continuous membrane system consisting of the nuclear envelope, flat sheets often studded with ribosomes, and a polygonal network of highly-curved tubules extending throughout the cell. Although protein and lipid biosynthesis, protein modification, vesicular transport, Ca2 +dynamics, and protein quality control have been investigated in great detail, mechanisms that generate the distinctive architecture of the ER have been uncovered only recently. Several protein families including the reticulons and REEPs/DP1/Yop1p harbor hydrophobic hairpin domains that shape high-curvature ER tubules and mediate intramembrane protein interactions. Members of the atlastin/RHD3/Sey1p family of dynamin-related GTPases interact with the ER-shaping proteins and mediate the formation of three-way junctions responsible for the polygonal structure of the tubular ER network, with Lunapark proteins acting antagonistically. Additional classes of tubular ER proteins including some REEPs and the M1 spastin ATPase interact with the microtubule cytoskeleton. Flat ER sheets possess a different complement of proteins such as p180, CLIMP-63 and kinectin implicated in shaping, cisternal stacking and cytoskeletal interactions. The ER is also in constant motion, and numerous signaling pathways as well as interactions among cytoskeletal elements, the plasma membrane, and organelles cooperate to position and shape the ER dynamically. Finally, many proteins involved in shaping the ER network are mutated in the most common forms of hereditary spastic paraplegia, indicating a particular importance for proper ER morphology and distribution in large, highly-polarized cells such as neurons. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Atlastin; Endoplasmic reticulum; Hereditary spastic paraplegia; Morphology; REEP; Reticulon;
The role of phospholipids in the biological activity and structure of the endoplasmic reticulum by Thomas A. Lagace; Neale D. Ridgway (2499-2510).
The endoplasmic reticulum (ER) is an interconnected network of tubular and planar membranes that supports the synthesis and export of proteins, carbohydrates and lipids. Phospholipids, in particular phosphatidylcholine (PC), are synthesized in the ER where they have essential functions including provision of membranes required for protein synthesis and export, cholesterol homeostasis, and triacylglycerol storage and secretion. Coordination of these biological processes is essential, as highlighted by findings that link phospholipid metabolism in the ER with perturbations in lipid storage/secretion and stress responses, ultimately contributing to obesity/diabetes, atherosclerosis and neurological disorders. Phospholipid synthesis is not uniformly distributed in the ER but is localized at membrane interfaces or contact zones with other organelles, and in dynamic, proliferating ER membranes. The topology of phospholipid synthesis is an important consideration when establishing the etiology of diseases that arise from ER dysfunction. This review will highlight our current understanding of the contribution of phospholipid synthesis to proper ER function, and how alterations contribute to aberrant stress responses and disease. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Phospholipids; Phosphatidylcholine; Cholesterol; Membranes;
The complexity of sphingolipid biosynthesis in the endoplasmic reticulum by Rotem Tidhar; Anthony H. Futerman (2511-2518).
Unlike the synthesis of other membrane lipids, sphingolipid synthesis is compartmentalized between the endoplasmic reticulum and the Golgi apparatus. The initial steps of sphingolipid synthesis, from the activity of serine palmitoyltransferase through to dihydroceramide desaturase, take place in the endoplasmic reticulum, but the further metabolism of ceramide to sphingomyelin and complex glycosphingolipids takes place mostly in the Golgi apparatus. Studies over the last decade or so have revealed unexpected levels of complexity in the sphingolipid biosynthetic pathway, mainly due to either the promiscuity of some enzymes towards their substrates, or the tight selectivity of others towards specific substrates. We now discuss two enzymes in this pathway, namely serine palmitoyltransferase (SPT) and ceramide synthase (CerS), and one lipid transport protein, CERT. For SPT and CERT, significant structural information is available, and for CerS, significant information has recently been obtained that sheds light of the roles of the specific ceramide species that are produced by each of the CerS. We consider the mechanisms by which specificity is generated and speculate on the reasons that sphingolipid biosynthesis is so complex. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Lipid; Sphingolipid; Ceramide; Ceramide synthase; Transmembrane protein; Golgi apparatus;
Take the (RN)A-train: Localization of mRNA to the endoplasmic reticulum by Orit Hermesh; Ralf-Peter Jansen (2519-2525).
Protein translocation into the endoplasmic reticulum (ER) generally requires targeting of mRNAs encoding secreted or membrane proteins to the ER membrane. The prevalent view is that these mRNAs are delivered co-translationally, using the signal recognition particle (SRP) pathway. Here, SRP delivers signal sequence-containing proteins together with associated ribosomes and mRNA to the SRP receptor present on the ER surface. Recent studies demonstrate the presence of alternative pathways to recruit mRNAs to ER or to specific subdomains of the ER independent of SRP or translation. Such targeting of specific mRNAs to the ER subdomains allows the cell to sort proteins before translocation or to ensure co-localization of ER and mRNAs at specific locations. Translation-independent association of mRNAs involves ER-linked RNA-binding proteins and represents an alternative pathway of mRNA delivery to the ER. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► mRNAs can be targeted to ER independent of their translation and SRP. ► Targeting of mRNAs to ER can occur via RNA-binding proteins like p180. ► Localization of mRNAs to ER subregions allows segregation of encoded proteins.
Keywords: Signal recognition particle; Cortical ER; p180; Prolamine; mRNA targeting;
Organization and function of membrane contact sites by Sebastian C.J. Helle; Gil Kanfer; Katja Kolar; Alexander Lang; Agnès H. Michel; Benoît Kornmann (2526-2541).
Membrane-bound organelles are a wonderful evolutionary acquisition of the eukaryotic cell, allowing the segregation of sometimes incompatible biochemical reactions into specific compartments with tailored microenvironments. On the flip side, these isolating membranes that crowd the interior of the cell, constitute a hindrance to the diffusion of metabolites and information to all corners of the cell. To ensure coordination of cellular activities, cells use a network of contact sites between the membranes of different organelles. These membrane contact sites (MCSs) are domains where two membranes come to close proximity, typically less than 30 nm. Such contacts create microdomains that favor exchange between two organelles. MCSs are established and maintained in durable or transient states by tethering structures, which keep the two membranes in proximity, but fusion between the membranes does not take place. Since the endoplasmic reticulum (ER) is the most extensive cellular membrane network, it is thus not surprising to find the ER involved in most MCSs within the cell. The ER contacts diverse compartments such as mitochondria, lysosomes, lipid droplets, the Golgi apparatus, endosomes and the plasma membrane. In this review, we will focus on the common organizing principles underlying the many MCSs found between the ER and virtually all compartments of the cell, and on how the ER establishes a network of MCSs for the trafficking of vital metabolites and information. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.► The endoplasmic reticulum makes several membrane contacts with various cellular organelles ► These contact sites typically serve in privileged calcium and lipid exchange reactions between compartments ► Tethering structures are required to establish and maintain such contacts ► Contact sites may be regulated in time and space to fulfill cellular needs ► Contact sites impact on the biogenesis, physiology and dynamics of most organelles.
Keywords: Membrane contact site; Organelle; Endoplasmic reticulum; Calcium; Lipid; Interorganelle communication;
The endoplasmic reticulum and junctional membrane communication during calcium signaling by Andy K.M. Lam; Antony Galione (2542-2559).
The endoplasmic reticulum is a major organelle in all eukaryotic cells which performs multiple functions including protein and lipid synthesis and sorting, drug metabolism, and Ca2 + storage and release. The endoplasmic reticulum, and its specialized muscle counterpart the sarcoplasmic reticulum, is the largest and most extensive of Ca2 + storage organelle in eukaryotic cells, often occupying in excess of 10% of the cell volume. There are three major components of Ca2 + storage organelles which mediate their major functions: Ca2 + uptake, mediated by pumps and exchangers; storage enhanced by luminal Ca2 + binding proteins, and Ca2 + mobilization mediated by specific ion channels. Ca2 + mobilization from the endoplasmic reticulum plays a central role in Ca2 + signaling. Through Ca2 + release channels in its membrane, the pervading and plastic structure of the endoplasmic reticulum allows Ca2 + release to be rapidly targeted to specific cytoplasmic sites across the whole cell. That several endoplasmic reticulum Ca2 + release channels are also activated by Ca2 + itself, contributes to endoplasmic reticulum membrane excitability which is the principal basis for generating spatio-temporal complex cellular Ca2 + signals, allowing specific processes to be regulated by this universal messenger. In addition, the endoplasmic reticulum forms discrete junctions with the plasma membrane and membranes of organelles such as mitochondria and lysosomes, forming nanodomains at their interfaces that play critical roles in Ca2 + signaling during key cellular processes such as cellular bioenergetics, apoptosis and autophagy. At these junctions key Ca2 + transport and regulatory processes come into play, and a recurring theme in this review is the often tortuous paths in identifying these mechanisms unequivocally. This article is part of a Special Issue entitled: Functional and structural diversity of endoplasmic reticulum.
Keywords: Endoplasmic reticulum; Calcium; Inositol trisphosphate; Cyclic ADP-ribose; NAADP; Organelle;