GAPDH: You think you know, but you have no idea – #GeneOTW

If you’ve ever taken a biology course, you should be familiar with glyceraldehyde-3-phosphate dehydrogenase—or at least its abbreviation: GAPDH.

GAPDH is a simple, highly conserved enzyme required for glycolysis, the process of turning glucose into energy.  Without GAPDH, glycolysis would be halted before energy (ATP) could be produced!  That would be a terrible thing, and even worse than being a pile of cells on the floor, we probably couldn’t exist at all!  The vital role and apparent simplicity of GAPDH—its transcripts vary little between species and are identical throughout the body—has led biologists to respectfully brush this humble gene aside as important but probably not that interesting1.

Over the past 20 years, however, scientists have been uncovering additional roles of GAPDH.  Several of these are illustrated in Figure 1.  Sirover (2011)2 describes GAPDH as “the prototype ‘moonlighting’ protein.” I like that.

 

Fig1 GAPDH

Figure 1. The functional diversity of GAPDH. From Sirover (2011).

Apoptosis, or “cell suicide,” is programmed cell death.  Interestingly, GAPDH is overexpressed and moves from the cytosol into the nucleus in cells undergoing apoptosis3 (Fig. 2).  There are many ways to kill a cell (or to make a cell kill itself), and GAPDH is involved in many of them.  For example, GAPDH is necessary for cell death induced by: androgen-depletion, oxidative stress, exposure to neurotoxins, and more4! Indeed, simple transfection of cells with GAPDH into cells can facilitate cell death5.

gapdh-gfp

Figure 2. GAPDH-GFP in healthy (A) and apoptotic (B) cells. In A, the dim areas within the cells are the nuclei. In B, the bright (/:) face within the cell is the nucleus.  It’s bright and /: because the GAPDH-GFP translocated there due to apoptosis…. :\  From Shashidharan et al. (1999).

How does this work? It is, you may have guessed, still unknown, but Zhai et al.6 recently proposed a mechanism for ischemia-induced cell death that may apply to other forms of cell death, as well. GAPDH binds to Siah, a nuclear localization signal-containing protein, before it moves into the nucleus. Once in the nucleus, the structure of GAPDH changes7. Zhai et al. suggest that nuclear GAPDH forms a complex with p53, a tumor suppressing protein, and activates a p53-mediated cell death pathway. When Zhai et al. blocked the formation of the GAPDH-p53 pathway in rats (with a really cool cell-penetrating peptide, HIV TAT), ischemia-induced apoptosis was inhibited! The GAPDH-p53 complex may therefore provide a novel target for stroke treatment!

Confusingly, despite the role of GAPDH in promoting apoptosis, it has recently been reported that overexpression GAPDH can actually protect cells from other types of cell death. Apoptosis occurs after mitochondrial outer membrane permealization (MOMP—womp womp! Fig. 3). After MOMP, both caspase-dependent cell death (apoptosis) and caspase-independent cell death (CICD) can occur. It was previously believed that MOMP was the “point of no return”: after MOMP, cell death could not be stopped. Unfortunately for those interested in cell destruction—that is, chemotherapists—GAPDH overexpression can block CICD, keeping cells (i.e., tumor cells) alive8.

F1.large

Figure 3. A bad case of the MOMPS. From Spierings et al. (2005)9.

How does GAPDH protect the cells? Jacquin et al. propose that GAPDH stabilizes Akt, a protein kinase that can block apoptosis.  Stabilizing Akt increases the expression of Bcl-xL, which protects mitochondria from MOMP.  This leaves just enough healthy mitochondria to allow cells to slowly recover from potential CICD!  This is great news for the cell, but understanding and disrupting this process could be vital for the development of more potent chemotherapeutic agents.

GAPDH is proving to be far more complex than biologists could have ever imagined. As a translational neuroscientists, I am excited to learn that GAPDH dysfunction probably plays a role in the development of mental illnesses10 and neurodegenerative disorders11 and may provide a target for treatment. But it’s just so complicated! Sigh…ence.

References: 

  1. Chuang, D.-M., Hough, C., & Senatorov, V. V. (2005). Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annual Review of Pharmacology and Toxicology, 45, 269–90. []
  2. Sirover, M.A. (2011). On the functional diversity of glyceraldehyde-3-phosphate dehydrogenase: biochemical mechanisms and regulatory control. Biochimica et Biophysica Acta1810(8), 741–51. []
  3. Shashidharan, P., Chalmers-Redman, R. M., Carlile, G. W., Rodic, V., Gurvich, N., Yuen, T., … Sealfon, S. C. (1999). Nuclear translocation of GAPDH-GFP fusion protein during apoptosis. Neuroreport, 10(5), 1149–1153. []
  4. Chuang, D.-M., Hough, C., & Senatorov, V. V. (2005). Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annual Review of Pharmacology and Toxicology45, 269–90. []
  5. Tajima, H., Tsuchiya, K., Yamada, M., Kondo, K., Katsube, N., & Ishitani, R. (1999). Over-expression of GAPDH induces apoptosis in COS-7 cells transfected with cloned GAPDH cDNAs. Neuroreport, 10(10), 2029–2033. []
  6. Zhai, D., Chin, K., Wang, M., & Liu, F. (2014). Disruption of the nuclear p53-GAPDH complex protects against ischemia-induced neuronal damage. Molecular Brain, 7(1), 20. []
  7. Chuang, D.-M., Hough, C., & Senatorov, V. V. (2005). Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annual Review of Pharmacology and Toxicology45, 269–90. []
  8. Jacquin, M. A., Chiche, J., Zunino, B., Bénéteau, M., Meynet, O., Pradelli, L. A., … Ricci, J.-E. (2013). GAPDH binds to active Akt, leading to Bcl-xL increase and escape from caspase-independent cell death. Cell Death and Differentiation, 20(8), 1043–54. []
  9. Spierings, D., McStay, G., Saleh, M., Bender, C., Chipuk, J., Maurer, U., & Green, D. R. (2005). Connected to death: the (unexpurgated) mitochondrial pathway of apoptosis. Science (New York, N.Y.), 310(5745), 66–7. []
  10. Johnson, A., Jaaro-Peled, H., Shahanib, N., Sedlakb, T. W., Zoubovsky, S., Burruss, D., … Gallagher, M. (2013). Cognitive and motivational deficits together with prefrontal oxidative stress in a mouse model for neuropsychiatric illness. Proceedings of the National Academy of Sciences of the United States of America, 110(30), 12462–12467. []
  11. Chuang, D.-M., Hough, C., & Senatorov, V. V. (2005). Glyceraldehyde-3-phosphate dehydrogenase, apoptosis, and neurodegenerative diseases. Annual Review of Pharmacology and Toxicology45, 269–90. []

1 Comment

  1. There’s a funny side effect of the ubiquity of GAPDH. Because it’s used as a control in so many situations, it overwhelms the signals of genes discussed in papers and around the intertubz!

    We were musing on that here: http://blog.openhelix.eu/?p=18261

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