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Role of O-Linked N-Acetylglucosamine Protein Modification in Cellular (Patho) Physiology

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Role of O-Linked N-Acetylglucosamine Protein Modification in Cellular (Patho) Physiology REVIEW ARTICLE ROLE OF O-LINKED N-ACETYLGLUCOSAMINE PROTEIN MODIFICATION IN CELLULAR (PATHO) PHYSIOLOGY AUTHORS O-GlcNAc and Cellular function John C. Chatham, Jianhua Zhang, Circadian Transcriptional Adam R. Wende regulation Regulation Epigenetics Mitochondrial Cellular Stress function Response CORRESPONDENCE CH OH 2 [email protected] O OGT Metabolic OH Intracellular regulation HO OH G signaling OH Protein Protein Learning and Memory Contractility Neurodegeneration Cardiac hypertrophy KEY WORDS OGA calcium; cancer; diabetes; genetics; metabolism Muscle fiber type Cancer/Tumor Cell survival Proliferation, Metastasis Metabolic homeostasis Insulin resistance O-GlcNAc and (patho)physiology CLINICAL HIGHLIGHTS The modification of proteins by sugars is one of the most common posttranslational modifications of proteins. Such modifications were believed to occur only on extracellular and secreted proteins and to consist of large branching structures comprising different sugar molecules. In the mid-1980s, a new modification was identified which consisted of a single N-acetylglucosamine moiety (O-GlcNAc) attached to serine and threonine residues of nuclear and cyto- plasmic proteins. Since its discovery, O-GlcNAc modification of proteins has been shown to affect numerous cellular functions, and changes in O-GlcNAc levels have been implicated in a wide variety of diseases. The goal of this review is to summarize our current knowledge of O-GlcNAc biology and its contribution to normal physiology and disease. CHATHAM ET AL., 2021, Physiol Rev 101: 427–493 July 30, 2020; Copyright © 2021 the American Physiological Society https://doi.org/10.1152/physrev.00043.2019 Physiol Rev 101: 427–493, 2021 First published July 30, 2020; doi:10.1152/physrev.00043.2019 REVIEW ARTICLE ROLE OF O-LINKED N-ACETYLGLUCOSAMINE PROTEIN MODIFICATION IN CELLULAR (PATHO) PHYSIOLOGY John C. Chatham, Jianhua Zhang, and Adam R. Wende Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama; and Birmingham Veterans Affairs Medical Center, Birmingham, Alabama Abstract In the mid-1980s, the identification of serine and threonine residues on nuclear and cytoplasmic proteins modified by a N-acetylglucosamine moiety (O-GlcNAc) via an O-linkage overturned the widely held assumption that glycosy- lation only occurred in the endoplasmic reticulum, Golgi apparatus, and secretory pathways. In contrast to tradi- tional glycosylation, the O-GlcNAc modification does not lead to complex, branched glycan structures and is rapidly cycled on and off proteins by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Since its discov- ery, O-GlcNAcylation has been shown to contribute to numerous cellular functions, including signaling, protein local- ization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. Dysregulation in O-GlcNAc cycling has been implicated in the progression of a wide range of diseases, such as diabetes, diabetic complications, cancer, cardiovascular, and neurodegenerative diseases. This review will outline our current under- standing of the processes involved in regulating O-GlcNActurnover,theroleofO-GlcNAcylation in regulating cellu- lar physiology, and how dysregulation in O-GlcNAc cycling contributes to pathophysiological processes. calcium; cancer; diabetes; genetics; metabolism CLINICAL HIGHLIGHTS 1. INTRODUCTION 427 2. REGULATION OF O-GLCNACYLATION 434 The modification of proteins by sugars is one of the most common fi fi 3. O-GLCNACYLATION AND ... 449 posttranslational modi cations of proteins. Such modi cations were believed to occur only on extracellular and secreted proteins and to 4. O-GLCNACYLATION IN ... 461 consist of large branching structures comprising different sugar mol- 5. CONCLUSIONS 470 ecules. In the mid-1980s, a new modification was identified which consisted of a single N-acetylglucosamine moiety (O-GlcNAc) attached to serine and threonine residues of nuclear and cytoplas- mic proteins. Since its discovery, O-GlcNAc modification of proteins 1. INTRODUCTION has been shown to affect numerous cellular functions, and changes in O-GlcNAc levels have been implicated in a wide variety of dis- eases. The goal of this review is to summarize our current knowl- 1.1. Brief History of O-GlcNAc edge of O-GlcNAc biology and its contribution to normal physiology and disease. The modification of proteins by carbohydrates, oth- erwise known as protein glycosylation, is the most However, in 1984, Torres and Hart (2)designedastudyto common posttranslational modification of proteins characterize terminal N-acetylglucosamine (GlcNAc) resi- and occurs in all cells and organisms (1). In the early dues on the surface of lymphocytes. Unexpectedly, they 1900s, there was considerable speculation that car- demonstrated that the majority of these terminal residues bohydrates were important parts of the structure of were localized inside the cell, and that rather than part of proteins, but the technology was lacking to provide extended glycan structures, they existed as a single definitive evidence. It was not until the 1960s and O-linked GlcNAc monosaccharide. 1970s that a better understanding of the structure Two years later, Holt and Hart (3) characterized the and function of these complex glycans on proteins cellular distribution of O-GlcNAc-modified proteins in rat started to emerge. Through the mid-1980s, the consen- liver cells, demonstrating that while they were found in sus was that protein glycosylation was restricted to nearly every cellular compartment, they were particu- extracellular proteins that originated in the endoplasmic larly enriched in the cytoplasm and nucleus. In 1987, a reticulum (ER), Golgi apparatus, and secretory pathway (1). monoclonal antibody to rat liver nuclear pore complex 0031-9333/21 Copyright © 2021 the American Physiological Society 427 CHATHAM ET AL. (clone RL2), appeared to primarily recognize O-linked of pathophysiological processes, such as diabetes, dia- O-GlcNAc groups (4). Hanover et al. (5)alsoreportednu- betic complications, cancer, cardiovascular, and neuro- clear pore proteins were modified by O-GlcNAc; however, degenerative diseases (19–24). the functional consequence of this modification was unclear at that time. During the same period, Holt et al. (6) 1.2. Differences between O-GlcNAc and identified both serine (Ser) and threonine (Thr) residues as Traditional Glycosylation the primary residues modified by O-GlcNAc. The fact that O-GlcNAcylated proteins were especially enriched in the Until the paradigm-changing study by Torres and Hart (2), nucleus raised the possibility that the modification could protein glycosylation was thought to be limited to extracel- be involved in protein transport into the nucleus; however, lular and excreted proteins. These proteins are processed the observation that cytoskeletal proteins in erythrocytes, via the ER-Golgi pathway, which contains a large number which lack a nucleus, were modified by O-GlcNAc sug- of glycosyltransferases that are responsible for creating gested other functions for this modification (7). In 1992, the N-andO-linked glycan structures. N-glycans are attached protein responsible for adding O-GlcNAc to proteins, O- to proteins as asparagine residues via an N-glycosidic GlcNAc transferase (OGT) was purified (8), but it was not bond; whereas, O-glycans are attached to Ser or Thr resi- until 1997 that the gene encoding OGT was identified, dues. These proteins are subject to processing and matu- revealing a glycosyltransferase that was unrelated to any ration by numerous glycosyltransferases, leading to stable other previously known glycosyltransferases (9). elongated and branched structures comprising a number In contrast to traditional protein glycosylation, it was of different monosaccharides. Glycosyltransferases are quickly established that O-GlcNAc modifications occurred estimated to account for at least 2% of the human ge- rapidly and reversibly (10), suggesting the existence of an nome (25).Theimportanceofthetightregulationofthis N-acetyl-glucosaminidase(s) responsible for its removal process is highlighted by the fact that mutations in genes from proteins. Dong et al. (11)purified an O-GlcNAcase related to glycosylation are associated with more than 100 that was distinctly different from lysosomal hexosamini- human genetic diseases, which are frequently associated dases, in that it was localized in the cytosol and was opti- with intellectual disabilities, as well as abnormalities in mally active at a neutral, rather than acidic, pH. In 2001, most organ systems (25). O-GlcNAcase was cloned and recognized to be identical Key distinguishing features of the O-GlcNAc modifica- to a previously known hexosaminidase C of unknown tion are that 1) with few exceptions, it occurs primarily on function, which specifically cleaved O-GlcNAc but not nuclear and cytoplasmic proteins; 2) it consists of a single O-linked N-acetylgalactosamine (O-GalNAc) from glyco- monosaccharide; 3) it is dynamic and rapidly reversible; 4) peptides (12). O-GlcNAcase was subsequently shown to it is catalyzed by a single unique O-GlcNAc transferase, have an identical sequence to a previously identified pro- and 5) it is removed by a glycohydrolase that is specificfor tein from meningioma patients called meningioma the removal of O-GlcNAc. It is of note that only very expressed antigen 5 (MGEA5) (13). recently have mutations in the OGT gene been linked to Over the decades since its discovery, O-GlcNAc
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