Cell mechanisms: the role and transport of proteins and lipids

15 November 2016

Professor David Banfield’s (Croucher Senior Research Fellowship, 2011) laboratory uses yeast as a primary model system to study fundamental questions in cell biology. His major interest lies in understanding how cells control the transport and traffic of proteins and lipids between the endoplasmic reticulum and the Golgi, two subcompartments in eukaryotic cells and components of the endomembrane network.

Banfield is an established cell biologist whose research on the structure and function of the Golgi apparatus has been published in the prestigious scientific journal Science, and contributed to the further investigation of recombinant protein therapeutics for the treatment of diseases such as diabetes.

“When I was a graduate student in Canada, I was working on something entirely different, focusing instead on molecular evolution of the blood coagulation process. I made a habit, however, to read papers by other researchers, as it enabled me to learn about different areas and stimulated my imagination and curiosity. I was drawn to this particular field of cell biology, namely protein and membrane trafficking, whilst reading a series of papers on the mechanism by which certain proteins are retained in the endoplasmic reticulum by Sir Hugh Pelham, under whom I subsequently trained and completed my post-doctoral studies.”

Retention of proteins in the Golgi

At the time of his Croucher Senior Research Fellowship in 2011, Banfield and his team had made the discovery that certain proteins are involved in controlling how a class of enzymes are retained in the Golgi. These enzymes, termed glycosyltransferases, mediate the process through which cells add different kinds of sugars to both proteins and lipids, and glycosylation is a common form post-translational modification by cells.

The prevailing question that had been asked for decades was how cells are able to compartmentalise these enzymes as the mechanism by which sugars are added to proteins is sequential and one modification necessarily precedes the other. While it had been known for many years that enzymes that control these individual events are found in discrete subcompartments of the Golgi, how they were localised in this way was not entirely clear.

Image of the Golgi apparatus, showing its characteristic "stack of pancakes" appearance.

Using yeast, he was able to identify the key protein that acts to retain a subset of glycosyltransferases in the Golgi, and reveal how disruption of this process, by mutations in the gene encoding this protein, disrupted the process of glycosylation.

Investigating GPI anchored proteins

Following their investigations on glycosyltransferase retention, Banfield and his team made yet another discovery that could impact the treatment of yeast infections.

He has begun researching another processing event that takes place on proteins which are linked to a particular lipid group called a glycosylphosphatidylinositol (GPI) anchor. 

Lipids are a major constituent of biological membranes and together with their associated proteins they form barriers between internal compartments as well as between cells. Some proteins are modified through the addition of lipids, and such modifications allow direct association between the protein and a particular biological membrane. The GPI anchor is one such lipid modification of a protein.

Banfield says that the addition of these anchors is an incredibly complex process as it involves different subsets of enzymes that trim or tailor-make individual GPI anchors on proteins. 

In situations where this process malfunctions, the resulting effects can be devastating, especially in humans, where defects in the synthesis or processing of GPI anchored proteins result in rare acquired diseases such paroxysmal nocturnal hemoglobinuria (a disorder of the blood) and the inherited disease hyperphosphatasia with mental retardation syndrome. 

For yeast however, GPI anchored proteins are important for the integrity of the cell wall, for formation of lipid domains on the limiting membrane of the cell, and for cytokinesis. Consequently a detailed understanding of the biogenesis and processing of GPI anchored proteins in yeast can serve as a vital tool in developing new drugs to treat fungal infections.

He says, “It is commonly known that there is a limited repertoire of drugs that can be used to treat bacterial infections. The situation is far worse when treating fungal infections as there aren’t many drugs available for treating such infections and amongst those that are available; their effectiveness is diminishing.”

While this aspect of Banfield’s research is currently a work in progress, he and his team have been investigating defects in the processing of GPI anchored proteins that result in inhibition of cell growth.

In bacteria cells, many of the drugs being used to treat bacterial infections aim to destroy the integrity of the cell wall and in doing so, these drugs cause bacterial cells to burst by osmotic lysis. The same principle (and process) can also be applied to yeast cells and to other fungi.

Banfield says, “Understanding the mechanism of action and substrate specificity of enzymes that synthesise GPI anchored proteins in yeast may therefore provide leads to the design of small molecules that might serve as effective pharmacological agents for treating fungal infections.”

Exploring basic cell biology

Banfield’s laboratory continues to explore basic questions in cell biology, in particular, questions that relate to mechanism(s) by which cells move proteins and lipids between cellular sub-compartments. 

While this particular area of cell biology is quite a mature field, the challenge for the next decade or so, according to Banfield, will be to understand how all the component parts of these nano-machines function together to maintain the robust compositional and functional integrity of the cell, and how defects in these cell biological processes lead to human disease.

Regarding his recent discoveries he says, “While I personally do not support the notion of having a directed or applied research program in the first instance, or having the application of scientific research being the primary goal, it is indeed very intellectually rewarding to make discoveries in basic science, and then imagine how they might be used to benefit mankind. We are foremost interested in understanding how cells work, but as a result of that, occasionally, if one is fortunate, you might discover something that can be used to benefit others and this [research] would be an example such an instance.”

Professor David Banfield is currently a professor of Life Sciences at the Hong Kong University of Science and Technology. He is a recognised authority on the structure and function of the Golgi apparatus and his research has been published in leading scientific journals such as Science. He obtained his undergraduate degree in Biochemistry and Biology from Simon Fraser University and a PhD degree in Biochemistry from the University of British Columbia. He continued his scientific career and education as a Human Frontiers and Canadian MRC Postdoctoral Research Fellow at the MRC Laboratory of Molecular Biology in Cambridge, England with Sir Hugh Pelham. He was awarded the Croucher Senior Research Fellowship in 2011. 

To view Banfield’s personal Croucher profile, please click here.