Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH): A Multifunctional Virulence Factor
GAPDH: A Multifunctional Moonlighting Protein in Eukaryotes and Prokaryotes
Michael A. Sirover
Department of Pharmacology, Temple University, School of Medicine, Philadelphia, USA
Glyceraldehyde-3-phosphate dehydrogenase (GAPDH, EC 18.104.22.168) is perhaps the archetypical example of a moonlighting protein. Although there were early indications of its functional diversity, it is only over the last two decades that its role as a premier multidimensional protein has become evident (Sirover 1999, 2005, 2011, 2014; Tristan et al. 2012). In eukaryotes, its diverse activities range in normal cells from nuclear tRNA export and the maintenance of genomic integrity, to cytoplasmic post-transcriptional control of gene expression and receptor mediated cell signaling, to membrane facilitation of iron metabolism, trafficking, and fusion (Fig. 8.1). The role of GAPDH in eukaryotic pathology extends from its fundamental role in apoptosis to its association with age-related neurodegenerative proteins to its distinctive expression during tumorigenesis. In both normal cell function and in cell pathology, eukaryotic GAPDH function requires either a defined subcellular localization or a dynamic change in its intracellular distribution. Lastly, its paradoxical functions in cell susceptibility as well as in cellular responses to oxidative stress indicate its physiological importance. In contrast, in prokaryotes such investigations focus primarily on its role in bacterial virulence which are based on its cell adhesion properties, its facilitation of iron metabolism in bacterial pathogenesis, and its targeted destruction of host cells. The first requires a specific membrane localization, the second involves not only membrane function but also, perhaps, its new role as an “iron scavenger,” and the third would, of necessity, involve the regulation of the complex pathway known as apoptosis. That being said, recent evidence identifies GAPDH not only as a bacterial virulence factor but also as a requirement for fungal, protozoal, or viral virulence. In each instance, selective GAPDH moonlighting functions are utilized as virulence mechanisms.
The functional diversity role of GAPDH begs a fundamental question. In the vernacular, what makes this moonlighting protein tick, what makes it what it is, and what permits it to perform such diverse functions in distinct parts of the
Moonlighting Proteins: Novel Virulence Factors in Bacterial Infections, First Edition. Edited by Brian Henderson.
© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.
Figure 8.1 Functional diversity of GAPDH.
eukaryotic or prokaryotic cell? Or, using scientific terminology, what permits one protein containing a single active site to perform such diverse functions in disparate subcellular locales? In this chapter we will consider the interrelationship between GADPH as a moonlighting protein and its role in bacterial virulence. As such, it is intended as an introduction to subsequent chapters which discuss in detail salient aspects of GAPDH-mediated bacterial pathogenesis. As such, it is hoped that the reader will gain insight into the mechanisms through which pathogenic bacteria have utilized GAPDH moonlighting properties to facilitate their successful infection and propagation. We shall also highlight areas in which the role of GAPDH in bacterial virulence has not been established, indicating the potential for future productive investigations.