Endoplasmic Reticulum Stress in Health and Disease

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2 Endoplasmic Reticulum Stress in Health and Disease

3 Patrizia Agostinis Afshin Samali (Eds.) Endoplasmic Reticulum Stress in Health and Disease 1 C

4 Editors Patrizia Agostinis Department of Cellular and Molecular Medicine K.U. Leuven Leuven, Belgium Afshin Samali School of Natural Sciences, Department of Biochemistry National University of Ireland Galway, Ireland ISBN ISBN (ebook) DOI / Springer Dordrecht Heidelberg New York London Library of Congress Control Number: Springer Science+Business Media Dordrecht 2012 No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Preface The Endoplasmic Reticulum (ER) is an organelle with extraordinary signaling and homeostatic functions. It is the organelle responsible for protein folding, maturation, quality control, and trafficking of proteins destined for the plasma membrane or for secretion into the extracellular environment. Failure, overloading or malfunctioning of any of the signaling or quality control mechanisms occurring in the ER may provoke a stress condition known as ER stress. Accumulating evidence indicates that ER stress may dramatically perturb interactions between the cell and its environment, and contributes to the development of human diseases, ranging from metabolic diseases and cancer to neurodegenerative diseases, or impacts therapeutic outcome. This book focuses on different aspects of ER stress. It starts with an introduction into the ER biology and the molecular bases of ER stress, the signaling pathways engaged and cellular responses to ER stress, including the adaptive Unfolded Protein Response (UPR), autophagy, as well as cell death. The reader will find much emphasis on transitions between different cellular responses and communication between different organelles (including ER-Golgi, ER-mitochondria and ER-nucleus communication). The book focuses on physiological responses of ER stress in pancreatic β cells and on major pathologies or pathological conditions which have been linked with ER stress. The first topic consists of chapters delineating the emerging role of ER stress in metabolic disease, such as obesity, Type 2 diabetes and cardiovascular disease. Next, the role of ER stress in inflammatory-based diseases and neurodegeneration is covered. Furthermore, the double-edged function of ER stress pathways in carcinogenesis is discussed. The last chapter describes how ER stress pathways can be targeted for therapeutic benefit. Altogether, these 19 chapters will provide the reader with the latest insights in the role of ER stress in pathophysiology. These chapters are presented by scientists at the forefront of scientific discovery. Their reviews will highlight the most exciting and innovative aspects of their particular areas of expertise in ER stress. Keywords: ER stress, Signal Transduction, Apoptosis, Autophagy, Carcinogenesis, Inflammation, Infection, Metabolic disease, Neurodegeneration, Therapy Related subjects: Biomedical Sciences, Cancer Research, Oncology, Metabolic disease, Inflammation v

6 Contents I Cellular Responses to ER Stress Biology of the Endoplasmic Reticulum Sandra JM Healy, Tom Verfaillie, Richard Jäger, Patrizia Agostinis and Afshin Samali A Tight-Knit Group: Protein Glycosylation, Endoplasmic Reticulum Stress and the Unfolded Protein Response Jared Q Gerlach, Shashank Sharma, Kirk J Leister and Lokesh Joshi ER Stress Signaling Pathways in Cell Survival and Death Tom Verfaillie, Richard Jäger, Afshin Samali and Patrizia Agostinis Endoplasmic Reticulum-Mitochondria Connections, Calcium Cross-Talk and Cell Fate: A Closer Inspection Riccardo Filadi, Enrico Zampese, Tullio Pozzan, Paola Pizzo and Cristina Fasolato ER Stress and UPR Through Dysregulated ER Ca 2 + Homeostasis and Signaling Tim Vervliet, Santeri Kiviluoto and Geert Bultynck Regulation of ER Stress Responses by micrornas Danielle E. Read, Ananya Gupta, Karen Cawley and Sanjeev Gupta ER Stress As Modulator of Autophagy Pathways María Salazar, Sonia Hernández-Tiedra, Mar Lorente and Guillermo Velasco Physiological ER Stress: The Model of Insulin-Secreting Pancreatic β-cells Mohammed Bensellam, Patrick Gilon and Jean-Christophe Jonas vii

7 viii Contents II ER Stress in Physiological and Pathological Conditions Pathological ER Stress in β Cells Bryan O Sullivan-Murphy and Fumihiko Urano Endoplasmic Reticulum Stress and the Unfolded Protein Response in Lipid Metabolism and Obesity Sana Basseri and Richard C. Austin ER Stress and Inflammation Abhishek D. Garg, Agnieszka Kaczmarek, Dmitri V. Krysko and Peter Vandenabeele ER Stress in Intestinal Inflammatory Disease Michal F. Tomczak, Arthur Kaser and Richard S. Blumberg Role of ER Stress in Dysfunction of the Nervous System Kohsuke Kanekura, Simin Lu, Kathryn L. Lipson and Fumihiko Urano Endoplasmic Reticulum (ER) Stress in Amyotrophic Lateral Sclerosis (ALS) Han-Jou Chen and Jackie de Belleroche Cardiovascular Disease and Endoplasmic Reticulum Stress Marek Michalak and Jody Groenendyk Signaling the Unfolded Protein Response in cancer Stéphanie Lhomond and Eric Chevet UPR Activation in Cancer Cells: A Double-Edged Sword Ethel R. Pereira, Amanda M. Preston and Linda M. Hendershot Contribution of ER Stress to Immunogenic Cancer Cell Death Abhishek D. Garg, Dmitri V. Krysko, Jakub Golab, Peter Vandenabeele and Patrizia Agostinis Current Advances in ER Stress Intervention Therapies Laurence A. Booth, Nichola Cruickshanks, Yong Tang, M. Danielle Bareford, Hossein A. Hamed, Paul B. Fisher, Steven Grant and Paul Dent Index

8 Part I Cellular Responses to ER Stress 1

9 Biology of the Endoplasmic Reticulum Sandra JM Healy, Tom Verfaillie, Richard Jäger, Patrizia Agostinis and Afshin Samali Contents 1 Introduction Structural Organization of the ER RER and SER Shape Dynamic Structure Association with Other Organelles ER Function Biosynthesis, Processing and Maturation of Proteins ERAD ER Export and Membrane Trafficking Calcium Storage Drug Detoxification Carbohydrate Metabolism Lipid Biosynthesis The ER Under Stress ER Stress Responses ER Stress in Physiology and Disease References P. Agostinis ( ) T. Verfaillie Cell Death Research & Therapy Unit, Department of Cellular and Molecular Medicine, Catholic University of Leuven, Leuven, Belgium Patrizia.agostinis@med.kuleuven.be S. J. Healy R. Jäger A. Samali Apoptosis Research Center, National University of Ireland, Galway, Ireland Afshin.samali@nuigalway.ie P. Agostinis, A. Samali (eds.), Endoplasmic Reticulum Stress in Health and Disease, DOI / _1, Springer Science+Business Media Dordrecht

10 4 S. J. Healy et al. Abstract Since its discovery in 1945, our knowledge of the structure and many functions of the endoplasmic reticulum (ER) has advanced at a phenomenal rate. Early studies focused on the structure, which was then followed by biochemical and functional studies associated with calcium storage and release from the ER, protein folding and secretion, ER associated degradation (ERAD) and ER stress responses. Currently there is a significant interest in the role of ER in such cellular processes as cell death, autophagy and cross-talk with other organelles. In this chapter we give an overview of the structural characteristics and biochemical functioning of the ER and describe its manifold roles in cellular physiology. Finally, we explain how the sensitive nature of the protein folding process in the ER enables this organelle to act as a sensor of a broad range of cellular stresses. Signals emanating from the stressed ER play central roles in differentiation processes, cellular homeostasis and cell death. Keywords Endoplasmic reticulum Protein folding Protein secretion Glycosylation Cell stress Apoptosis Autophagy Physiology Unfolded protein response Calcium storage Lipid biosynthesis Drug detoxification Membrane trafficking Carbohydrate metabolism Golgi ERAD Abbreviations ATF Activating transcription factor CNX Calnexin COPII Coat protein II CRT Calreticulin CYP Cytochrome p-450 ER Endoplasmic reticulum ERAD ER associated degradation ERAF ER associated folding GRP Glucose regulated protein GSH Glutathione HSP Heat shock protein IP3R Inositol trisphosphate receptor IRE1 Inositol-requiring enzyme 1 PDI Protein disulfide isomerase PERK Pancreatic ER kinase-like ER kinase PM Plasma membrane PPIs Peptidyl-prolyl cis-trans isomerase RER Rough ER RYR Ryanodine receptor SER Smooth ER

11 Biology of the Endoplasmic Reticulum 5 SERCA SNARE SR SREBPs TAC ter UGGT UGT UPR Sarco-endoplasmic reticulum activated Ca 2 + pump Soluble N-ethylmaleimide-sensitive factor attachment protein receptor Sarcoplasmic reticulum Sterol regulatory element binding proteins Tip attachment complex Transitional ER UDP-Glc:glycoprotein glucosyltransferase UDP-glucuronyl transferase Unfolded protein response 1 Introduction In 1945, using new techniques developed for appropriate fixation and mounting of samples for electron microscopy, Keith Porter and colleagues observed the presence of a lace-like reticulum in the cytoplasm of cultured avian cells [1]. The reticulum network appeared to be part of the ground substance of the cytoplasm and consisted of interconnected strands and vesicles of approx μm dimensions and relatively low density. This newly discovered cytoplasmic organelle was later studied in full detail in various cells by Porter and colleagues who coined the term endoplasmic reticulum (ER) because of its general morphology and its intracellular location. These studies further showed that the cytoplasmic basophilia which was long known to light microscopists, was attributable to the presence of what is now known as rough ER (RER) in active acinar cells. The ER is the biggest organelle in most cell types. It is a complex organelle composed of a single continuous membrane that is comprised of the nuclear envelope, flattened peripheral sheets studded with ribosomes and a complex network of smooth tubules that extends throughout most of the cell. The ER has many different cellular functions and its heterogeneous structures enable it to carry out its many functional roles in the cell. As such the ER may also correctly be described as an assembly of several, distinct membrane domains that execute diverse functions. At the morphological level, the ribosome studded ER membrane, known as the RER, tends to form large flattened sheets with the ribosomes bound to the cytosolic face of the ER membrane. Proteins entering the secretory pathway as well as prospective transmembrane proteins are synthesized by these ribosomes and cotranslationally inserted through the pore complex into the ER lumen where most of the folding and post-translational processing of secretory pathway proteins takes place. The smooth ER (SER) does not have attached ribosomes and mainly consists of tubular structures. It is the primary site for the detoxification of drugs, fatty acid and steroid biosynthesis and Ca 2 + storage [2]. However, the RER and SER are continuous and material can travel between them. While most cells contain both types of ER, the proportion of each can vary considerably and depends to a large extent on the needs or function of a particular cell. For example, cells involved in

12 6 S. J. Healy et al. synthesizing large amounts of protein for secretion, e.g., antibody producing B cells and insulin secreting pancreatic β-cells, will have a large RER network while cells producing steroid hormones (e.g, cells of adrenal cortex) will contain extensive SER networks. All cells also have a transitional ER (ter) which is biochemically and morphologically distinct from the RER and SER, and is involved in packaging proteins for transport from the ER to the Golgi. Recently, the importance of the ER architecture for its specialized functions has been highlighted and it is now recognized that the mechanisms that generate and maintain the diverse structures of this organelle are essential for proper ER function [3]. In this Chapter we will briefly review current understanding of ER structure (for a more in depth review see [3]) and examine its functional roles in the cell. We will then review how factors that disrupt ER function lead to ER stress, which triggers a stress response. This stress response aims to restore ER homeostasis but can also induce apoptosis if ER stress is overwhelming. 2 Structural Organization of the ER 2.1 RER and SER The structurally distinct ER domains include the nuclear envelope and the peripheral ER. In this chapter we will focus on the peripheral ER. The peripheral domain consists of the rough ribosome bound sheet-like RER and the smooth highly convoluted extensive network of interconnected ER tubules of the SER; While many proteins are found throughout both SER and RER (e.g., protein folding chaperones such as GRP94, GRP78, calnexin, calreticulin and BAP31 [4]), each of the ER domains is also enriched in proteins required for their specific functions [5, 6]. For example, all cells need to synthesize, fold and process new membrane or secretory proteins and therefore all cells have RER which is enriched in proteins to carry out this function (e.g., ribophorins I and II [7], Sec61, nascent chain associated proteins (NAC) and the translocon-associated protein (TRAP)). Moreover, highly secretory cells such as the β-cells of the pancreas or immunoglobulin producing B cells, possess an extensive RER which enables the cell to maintain high levels of protein production. The SER on the other hand, is especially abundant in certain cell types such as liver cells, steroid producing cells, muscle cells and neurons. Interestingly, the primary activities of the SER are very different in different cell types. For example, in liver cells, the SER is important for detoxification of xenobiotic substances for which specific isoforms of cytochrome P450 are required. In muscle cells, the SER is enriched in proteins such as RyR1, DHPR, Triadin, junctin and SERCA which enable the release and uptake of Ca 2 + for muscle contraction. In steroid hormone producing cells such as those of the adrenal cortex or sex organs, the SER is the site of steroid biosynthesis and members of the cytochrome P450 family are also required for this process. Therefore, to some extent, the SER is a cell-type specific

13 Biology of the Endoplasmic Reticulum 7 suborganelle. The mechanisms by which the RER and SER maintain their distinct protein compositions, facilitating their specific functions, are currently unclear. 2.2 Shape Typically, ER membranes are built up as sheets or tubules. Lipid bilayers by themselves tend to remain flat although if lipids are asymmetrically distributed, it could possibly suffice to generate curved structures. However, there is little evidence that this occurs in vivo and it is thought that active mechanisms are required to generate the curved structures of the RER and SER [4]. Current evidence indicates that specific proteins (such as the DP1/PEEPs/Yop1 proteins and the reticulon protein family) are required to generate the high curvature membranes of the ER and do so by a number of different mechanisms (e.g., membrane deformation by force generating proteins, use of scaffolding proteins to bend membranes, hydrophobic membrane proteins causing hydrophobic wedges resulting in ER curvature, attachment to polymerizing microtubules) [8, 9]. This suggests that there are specific proteins or families of proteins that are required to generate and maintain the ER sheets and tubules, while other proteins (such as p97/p47/vcip135 complex, syntaxin 18 and BNIP1/Sec20) have been implicated in the fusion of tubules to form the interconnected ER network [10]. 2.3 Dynamic Structure The nature of the peripheral ER network is highly dynamic, consisting of cisternal sheets, linear tubules and three way junctions that are constantly being rearranged while maintaining the characteristic structure of the RER and SER. This dynamic nature may be facilitated through interactions with the cytoskeleton, plasma membrane or other organelles. Evidence that the cytoskeleton is important for ER structure can be inferred from the fact that treatment of cells with nocodazole (a microtubule disruptor) causes collapse of the ER [11]. Live cell imaging has demonstrated that the dynamic movement of the ER is achieved by tracking along microtubules in two mechanistically different ways the tip of the ER tubule can attach to the tip of a dynamic tubule so as the microtubule grows or shrinks, so does the ER tubule (tip attachment complex (TAC)). Alternatively, the ER tubules seem to jump onto the shaft of the microtubule and slide along. The movement of ER by sliding appears to be much faster than by TAC and the two mechanisms may have different functional consequences [12]. 2.4 Association with Other Organelles Some regions of the ER associate tightly with other organelles in the cell, including the Golgi, mitochondria, peroxisomes, vacuoles and the plasma membrane (PM).

14 8 S. J. Healy et al. These interactions are functionally important and highlight the need for an extensive ER network spread throughout the cytoplasm. The interaction between ER and mitochondria is mediated by specific protein complexes that facilitate interorganellar molecular exchange and molecular signaling, which is important for several physiological processes like Ca 2 + signaling, apoptosis regulation and lipid transfer [13]. The ER can also form direct contacts with the Golgi to facilitate the nonvesicular transport of some lipids between these two organelles. The short distance that exists between the far reaches of the ER network and the PM suggests that protein complexes may also form bridges between these membranes. The transport of sterols and phospholipids from the ER to the PM is likely to be direct and does not rely on vesicular transport between the ER and Golgi because these lipids accumulate more rapidly on the PM than would be predicted if they were transported predominantly through the secretory pathway [14]. However the proteins that may be involved in this process are currently unknown. Additionally, interactions of the ER with the PM are important for regulating intracellular Ca 2 + stores [15]. The interaction of the ER with other organelles is a way for the ER to communicate with the rest of the cell and further studies are required to establish how these connections are made and regulated. 3 ER Function 3.1 Biosynthesis, Processing and Maturation of Proteins Soluble proteins for the endomembrane system as well as proteins for export and membrane proteins are synthesized by ribosomes attached to the cytosolic side of the RER (Fig. 1). In fact approximately one third of all proteins in eukaryotes are targeted to the secretory pathway, and proteins involved in the synthesis and translocation of polypeptides are one of the largest functional groups of ER proteins [5]. As the polypeptide is being synthesized on the ribosome, an amino terminal signal sequence directs it to the Sec61 translocon, a protein conductive channel, where protein translocation across the ER membrane occurs [16, 17]. It consists of two essential subunits; a channel forming multispanning membrane protein Sec61p/ Sec61α and a tail anchored Sss1p/Sec61γ which has been proposed to clamp the channel. Once synthesized, proteins need to be properly folded and processed into their native conformation this is carried out by specific enzymes which catalyze the co-translational and post-translational modification of proteins and by chaperones that facilitate the correct folding of the newly synthesized protein. Protein modifications may include disulfide-bond formation, cleavage of the ER signalrecognition peptide, N-linked glycosylation (see Chap. 2) and addition of some type of anchor, tethering the protein to the membrane. The RER lumen is optimal for protein folding and maturation because, unlike the rest of the cell, it is an oxidizing environment which promotes the formation of disulphide bonds and it contains a complex network of protein chaperones and folding enzymes (foldases) comprising

15 Biology of the Endoplasmic Reticulum 9 Fig. 1 Main functions of the ER. Through SEC61 channels proteins are cotranslationally imported into the ER lumen where they become glycosylated (only relevant sugar residues shown for clarity; G glucose, M mannose). Through the action of glucosidases I and II two terminal glucoses (G) are removed such that nascent protein chains are monoglucosylated and can bind to calreticulin (CRT) and calnexin (CNX), which initiates the folding process. Interaction with CRT and CNX is terminated by removal of the glucose mediated by glucosidase II. Whereas correctly folded proteins then enter COPII-coated vesicles destined for transport to Golgi, unfolded proteins are glucosylated again by UGGT and reenter the Calnexin cycle. Terminally misfolded proteins are demannosylated in the middle branch of the oligosaccharide, targeting them to ERAD. If unfolded proteins accumulate they are bound by GRP78 and activate the ER stress receptors triggering the UPR. Ca 2+ storage is mediated through Ca 2+ channels such as SERCA, and Ca 2+ can be released via IP3 receptors (IP3R). Specialized functions of the smooth ER (SER) are listed in the text box