GAPDH (Loading Control)

This gene encodes a member of the glyceraldehyde-3-phosphate dehydrogenase protein family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The product of this gene catalyzes an important energy-yielding step in carbohydrate metabolism, the reversible oxidative phosphorylation of glyceraldehyde-3-phosphate in the presence of inorganic phosphate and nicotinamide adenine dinucleotide (NAD). The encoded protein has additionally been identified to have uracil DNA glycosylase activity in the nucleus. Also, this protein contains a peptide that has antimicrobial activity against E. coli, P. aeruginosa, and C. albicans. Studies of a similar protein in mouse have assigned a variety of additional functions including nitrosylation of nuclear proteins, the regulation of mRNA stability, and acting as a transferrin receptor on the cell surface of macrophage. Many pseudogenes similar to this locus are present in the human genome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

Glyceraldehyde-3-Phosphate Dehydrogenase

Has both glyceraldehyde-3-phosphate dehydrogenase and nitrosylase activities, thereby playing a role in glycolysis and nuclear functions, respectively (PubMed:3170585, PubMed:11724794).

Glyceraldehyde-3-phosphate dehydrogenase is a key enzyme in glycolysis that catalyzes the first step of the pathway by converting D-glyceraldehyde 3-phosphate (G3P) into 3-phospho-D-glyceroyl phosphate (PubMed:3170585, PubMed:11724794).

Modulates the organization and assembly of the cytoskeleton (By similarity).

Facilitates the CHP1-dependent microtubule and membrane associations through its ability to stimulate the binding of CHP1 to microtubules (By similarity).

Component of the GAIT (gamma interferon-activated inhibitor of translation) complex which mediates interferon-gamma-induced transcript-selective translation inhibition in inflammation processes (PubMed:23071094).

Upon interferon-gamma treatment assembles into the GAIT complex which binds to stem loop-containing GAIT elements in the 3'-UTR of diverse inflammatory mRNAs (such as ceruplasmin) and suppresses their translation (PubMed:23071094).

Also plays a role in innate immunity by promoting TNF-induced NF-kappa-B activation and type I interferon production, via interaction with TRAF2 and TRAF3, respectively (PubMed:23332158, PubMed:27387501).

Participates in nuclear events including transcription, RNA transport, DNA replication and apoptosis (By similarity).

Nuclear functions are probably due to the nitrosylase activity that mediates cysteine S-nitrosylation of nuclear target proteins such as SIRT1, HDAC2 and PRKDC (By similarity).

Antimicrobial humoral immune response mediated by antimicrobial peptide Source: UniProtKB
Cellular response to interferon-gamma Source: UniProtKB
Defense response to fungus Source: UniProtKB
Glucose metabolic process Source: InterPro
Glycolytic process Source: GO_Central
Killing by host of symbiont cells Source: UniProtKB
Killing of cells of other organism Source: UniProtKB
Microtubule cytoskeleton organization Source: UniProtKB
Negative regulation of endopeptidase activity Source: UniProtKB
Negative regulation of translation Source: UniProtKB
Neuron apoptotic process Source: UniProtKB
Peptidyl-cysteine S-trans-nitrosylation Source: UniProtKB
Positive regulation of cytokine production Source: UniProtKB
Positive regulation of I-kappaB kinase/NF-kappaB signaling Source: UniProtKB
Positive regulation of type I interferon production Source: UniProtKB
Protein stabilization Source: UniProtKB
Regulation of macroautophagy Source: ParkinsonsUK-UCL

Cytosol; Cytoskeleton; Nucleus; Perinuclear region; Membrane. Translocates to the nucleus following S-nitrosylation and interaction with SIAH1, which contains a nuclear localization signal (By similarity). Postnuclear and Perinuclear regions (PubMed:12829261).

S-nitrosylation of Cys-152 leads to interaction with SIAH1, followed by translocation to the nucleus (By similarity). S-nitrosylation of Cys-247 is induced by interferon-gamma and LDL(ox) implicating the iNOS-S100A8/9 transnitrosylase complex and seems to prevent interaction with phosphorylated RPL13A and to interfere with GAIT complex activity (PubMed:22771119, PubMed:25417112).
ISGylated.
Sulfhydration at Cys-152 increases catalytic activity.
Oxidative stress can promote the formation of high molecular weight disulfide-linked GAPDH aggregates, through a process called nucleocytoplasmic coagulation. Such aggregates can be observed in vivo in the affected tissues of patients with Alzheimer disease or alcoholic liver cirrhosis, or in cell cultures during necrosis. Oxidation at Met-46 may play a pivotal role in the formation of these insoluble structures. This modification has been detected in vitro following treatment with free radical donor (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide. It has been proposed to destabilize nearby residues, increasing the likelihood of secondary oxidative damages, including oxidation of Tyr-45 and Met-105. This cascade of oxidations may augment GAPDH misfolding, leading to intermolecular disulfide cross-linking and aggregation.
Succination of Cys-152 and Cys-247 by the Krebs cycle intermediate fumarate, which leads to S-(2-succinyl)cysteine residues, inhibits glyceraldehyde-3-phosphate dehydrogenase activity. Fumarate concentration as well as succination of cysteine residues in GAPDH is significantly increased in muscle of diabetic mammals. It was proposed that the S-(2-succinyl)cysteine chemical modification may be a useful biomarker of mitochondrial and oxidative stress in diabetes and that succination of GAPDH and other thiol proteins by fumarate may contribute to the metabolic changes underlying the development of diabetes complications.
(Microbial infection) Glycosylated by C.rodentium protein NleB, enteropathogenic E.coli protein NleB1 and S.typhimurium protein Ssek1: arginine GlcNAcylation prevents the interaction with TRAF2 and TRAF3 (PubMed:23332158, PubMed:27387501, PubMed:28522607). This leads to reduced ubiquitination of TRAF2 and TRAF3, and subsequent inhibition of NF-kappa-B signaling and type I interferon production, respectively (PubMed:23332158, PubMed:27387501).