The Writers, Readers, and Erasers in Redox Regulation of GAPDH

Abstract

Glyceraldehyde 3–phosphate dehydrogenase (GAPDH) is a key glycolytic enzyme, which is crucial for the breakdown of glucose to provide cellular energy. Over the past decade, GAPDH has been reported to be one of the most prominent cellular targets of post-translational modifications (PTMs), which divert GAPDH toward different non-glycolytic functions. Hence, it is termed a moonlighting protein. During metabolic and oxidative stress, GAPDH is a target of different oxidative PTMs (oxPTM), e.g., sulfenylation, S-thiolation, nitrosylation, and sulfhydration. These modifications alter the enzyme’s conformation, subcellular localization, and regulatory interactions with downstream partners, which impact its glycolytic and non-glycolytic functions. In this review, we discuss the redox regulation of GAPDH by different redox writers, which introduce the oxPTM code on GAPDH to instruct a redox response; the GAPDH readers, which decipher the oxPTM code through regulatory interactions and coordinate cellular response via the formation of multi-enzyme signaling complexes; and the redox erasers, which are the reducing systems that regenerate the GAPDH catalytic activity. Human pathologies associated with the oxidation-induced dysregulation of GAPDH are also discussed, featuring the importance of the redox regulation of GAPDH in neurodegeneration and metabolic disorders.

Glutathione in Protein Redox Modulation through S-Glutathionylation and S-Nitrosylation

“…On the contrary, DNA-activated protein kinase (DNA-PK), which is involved in DNA repair, is activated by S-nitrosylation with the participation of GAPDH-SNO [88,97]. In response to stress, GAPDH is translocated into the mitochondria, where it transnitrosylates Hsp60, acetyl-CoA thiolase, and VDAC1, thus affecting membrane permeability, the regulation of mitochondrial function, and cell death [98,99].…”

Reference genes for mesangial cell and podocyte qPCR gene expression studies under high-glucose and renin-angiotensin-system blocker conditions

“…A previous study on reference genes for rat mesangial cells found ACTB to be one of the best reference genes for this cell line under high glucose conditions, in conformity with our findings [ 17 ]. Glyceraldehyde 3-phosphate dehydrogenase ( GAPDH ), although it is reported to be involved in cellular survival, apoptosis and DNA repair, is mainly known to express a cellular energy enzyme determinant of the glycolytic process, functioning as a catalyzer of triose phosphate oxidation and, for this reason, ubiquitously distributed in all cell types [ 46 , 47 ].…”

Extensive Anti-CoA Immunostaining in Alzheimer’s Disease and Covalent Modification of Tau by a Key Cellular Metabolite Coenzyme A

“…To date, over 2200 CoAlated proteins have been identified in prokaryotic and eukaryotic cells exposed to oxidative or metabolic stress. Protein CoAlation has been shown to regulate the activity and subcellular localization of modified proteins, protect oxidized cysteine residues from irreversible overoxidation, and to induce conformational changes (Gout, 2018(Gout, , 2019Bakovic et al, 2019;Tossounian et al, 2020;Tsuchiya et al, 2020;Yu et al, 2021). The antioxidant function of CoA and protein CoAlation in pathologies associated with oxidative stress, such as neurodegeneration, cancer, and diabetes, remains to be investigated.…”