Visiting the ER: The endoplasmic reticulum as a target for therapeutics in traffic related diseases☆
Introduction
The endoplasmic reticulum (ER) is the first compartment of the secretory pathway. The ER contributes extensive membrane surfaces in the cell extending from the nuclear envelop to the cell periphery [1]. In highly elongated and polarized cells such as neurons the ER spreads from the cell body throughout the dendrites and the axon [2], [3]. The ER is polarized, where ribosome-studded membranes (rough ER) are in continuity with smooth membranes that provide surfaces for vesicle formation at ER exit sites. The elaborate architecture supports a variety of key activities in the cell including the biosynthesis of lipids, folding and assembly of proteins and control of Ca2+ signaling and homeostasis [4]. These basic activities are monitored by ER receptors that can initiate and regulate elaborated molecular cascades. ER derived signaling cascades dramatically manipulate gene expression to adjust ER functions with cellular needs and control general cell physiology. ER signaling can also culminate in programmed destruction of the cell to support tissue and organism needs [5]. The elaborate activities of the ER are prone to mistakes that lead to development of diseases [6], [7], [8] (Table 1). Therefore, understanding the basic principles of ER functions will define molecular targets for the development of future therapeutics. In this review I will summarize the basic functions of the ER to illuminate how disease can arise from mistakes in ER functions [6], [7], [8]. Current avenues and future directions in development of therapeutics for ER-derived diseases will be summarized.
Section snippets
The ER processor: two execution pathways
Early morphological and biochemical studies uncovered the role of ER-associated ribosomes and the translocon in mediating the co-translational insertion of newly synthesized polypeptides into the ER [9], [10], [11], [12], [13]. These nascent polypeptides fold and assemble into proteins that are targeted for expression at the plasma membrane, directed to intracellular organelles or destined for secretion. It is estimated that nearly a third of the human genome product is processed through the ER
Loss of function
Folding problems in the ER compromise the traffic and function of a variety of proteins expressed in different organs. Mutations in proteins that hinder their proper folding are a common reason for the development of ER processing diseases. The outcome of such mutations in many cases is the elimination of the mutated proteins by degradation in the ER.
For example, a deletion of phenylalanine (F) at position 508 in CFTR is the cause for disease in up to 80% of cystic fibrosis patients [26], [27].
Protein folding in the ER: the basic ingredients
Protein folding is at the basis of the ER execution pathways. Guided by the primary information encoded in the polypeptide backbone, proteins inserted in the ER undergo chaperone-assisted folding to assume an energetically stable conformation. Thus hydrophobic surfaces are packed within the protein and intra-molecular interactions including salt bridges and disulfide bonds are formed to stabilize a folded configuration and minimize the free energy associated with the newly synthesized
Decision making in the ER: timing the folding reaction
The ER contains high concentrations of unfolded peptides. Molecular quality control is required to differentiate between proteins on a productive folding pathway and those that cannot achieve the stability required to egress through the secretory pathway. Non-folding proteins are removed by degradation to prevent accumulation and possible toxic aggregation. Understanding the rules that govern quality control is key to the understanding of decisions in the ER that lead to the development of
ER execution I: degradation
When a protein fails to achieve energetically stable conformation it is routed for degradation. Importantly, degradation of proteins in the ER (ERAD; ER associated degradation) is a specific and targeted process. Early studies demonstrated that viruses specifically manipulate ERAD to evade immune surveillance. For example, the cytomegalovirus expresses two proteins, US2 and US11, in the ER to specifically induce the degradation of the major histocompatibility complex class 1 (MHC1) heavy chain
ER execution II: COPII-mediated ER export
Newly synthesized proteins that fold, assemble and assume a stable conformation are recognized and sorted into secretory vesicles by the activity of the cytosolic coat protein complex II (COPII). COPII also serves as a mechanical device that bends and deforms the membranes to extrude buds and release vesicles [24].
The COPII coat is composed of three cytosolic components, the small GTPase Sar1, the Sec23 and Sec24 protein complexes and the Sec13 and Sec31 protein complexes. These complexes are
ER sensors: monitoring cargo folding in the ER
The development of diseases such as juvenile Parkinson, Alzheimer (and other forms of neurodegenerative diseases) or forms of type I and type II diabetes (Table 1) can be derived from the ability of the ER to manipulate cell and organ physiology (gain of functions). An elaborated multi phase genetic program is activated when protein folding, degradation and/or export from the ER are perturbed [49], [153]. Protein folding deficiencies can be derived from mutations in individual cargo proteins
Stabilization of protein folding
At the heart of protein processing diseases are problems in protein folding. Promoting protein folding in the ER is a key therapeutic target to address a variety of ER-derived diseases (Table 1). In many cases, mutations associated with specific protein misfolding lead to reduced stability of folding intermediates in the ER, but do not preclude folding if further stabilization is provided. One simple test utilized to determine the severity of a folding defect is based on the ability of a mutant
Acknowledgements
MA thanks Drs. L.M. Traub and J.L. Brodsky for critically reading the manuscript. Supported by NIH grant DK062318 (MA) and a grant from the American Health Assistance Foundation (MA).
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Organelle-Specific Targeting in Drug Delivery and Design".