Using yeast to dissect disease pathways
Lead researcher: Dr Chris MacDonald, Department of Biology
Cell surface membrane proteins play key roles in a broad range of physiological processes and form the largest class of approved drug targets.
Despite this, fundamental questions regarding their regulation remain unanswered. Surface proteins are continually internalized to endosomes, where they can be targeted for degradation or follow recycling routes back to the surface (Figure 1).
Recycling can therefore control surface activity of a diverse range of proteins. Despite this, we have limited understanding of the mechanisms that regulate these recycling pathways . The budding yeast system is a powerful genetic model that has famously been used to identify protein machinery responsible for various processes and intracellular trafficking pathways.
Using yeast, we have shown recycling can occur via the Golgi in a pathway that relies on ubiquitination [2,3]. Alternatively, recycling can occur independently of ubiquitination [4,5], in a pathway that appears to bypass the Golgi . To study this latter pathway, we performed a comprehensive genetic screen that identified many novel and conserved participants in the recycling pathway . Current projects are aimed at taking advantage of the genetic and cell biological framework developed to study recycling and elucidate the molecular mechanisms of these novel factors. We aim to reveal fundamental trafficking paradigms that relate to cell surface recycling and test these models in cultured mammalian cells.
We are also interested in the trafficking of cell surface membrane proteins from the early secretory pathway, as they are exported from the endoplasmic reticulum (ER). There are many disease-causing mutations that compromise folding of proteins at the ER. This can be detrimental in two main ways. Firstly, the accumulation of such defective proteins (many of which are prone to aggregation due to their misfolded state) are toxic to the cell. Secondly, ER retention effectively depletes the surface of that protein. Much of the machinery that regulates the secretory pathway is highly conserved, so yeast can be used as a model to understand factors involved in retention and export from the ER (Figure 2).
- Laidlaw & MacDonald Biochemical Transactions (2018)
- MacDonald et al. Traffic (2017)
- Xu et al. eLife (2017)
- MacDonald et al. EMBO Reports (2012)
- MacDonald et al. Developmental Cell (2015)
- MacDonald & Piper Journal of Cell Biology (2017)