I was appointed to a lecturing post at Sheffield Hallam in 2013. Previous to this I carried out postdoctoral research at the University of Manchester. My research interests include the regulation of protein synthesis. My teaching interests include the development of innovative teaching methods for developing practical skills for scientists and I am the module leader for the year 1 Professional and Scientific Practice - Labs module. I am also the admissions tutor for the Department of Biosciences and Chemistry and the local ambassador for the Biochemical Society.
I was awarded my BA (Mod) in Microbiology from Trinity College Dublin, Ireland. I continued my studies at Trinity College and completed a PhD entitled 'The regulation of 3' end processing under the supervision of Prof Ursula Bond. I continued with Prof Bond as a research associate investigating the adaptation of yeast brewing stress to high wort environments before moving initially to UMIST and then to The University of Manchester, where I carried out postdoctoral research on the impact of environmental stress on translation initiation in yeast, in the lab of Dr Mark Ashe.
In 2013 I took up the position of Senior Lecturer at Sheffield Hallam University, my research focusses on how the localisation of proteins within cells impacts upon their function. It is becoming increasingly evident that compartmentalisation of the cytoplasm of cells into discrete regions, enables efficient control of translation initiation. Understanding the regulation of this localisation is a key theme within my research. In particular, I am interested in how the compartmentalisation of translation initiation factors within a cell impact upon their function and how this may be important in addressing the molecular mechanisms behind diseases classically associated with translational deregulation. In particular, the neurodegenerative disease childhood ataxia with central nervous system hypomyelination (CACH) or leukoencephalopathy with vanishing white matter (VWM) has been linked to mutations in the translation initiation complex eIF2B and the molecular mechanisms behind how these mutations may impact upon these complexes of eIF2B is a key question within my research.
Professional and Scientific Practice labs and skills
Essential Biosciences, Advanced Cell Biology, Immunology and Microbiology
My research focusses on the control of translation initiation in response to stress conditions in the budding yeast Saccharomyces cerevisiae. During translation initiation the Met-tRNAi is recruited to the 40S ribosomal subunit in a ternary complex with eIF2-GTP. On identification of an AUG codon the eIF2-GTP is hydrolysed releasing eIF2-GDP from the complex. One of the key regulatory steps in the translation initiation pathway involves the recycling of inactive GDP-bound eIF2 into active GTP-bound eIF2. This step is catalysed by the guanine nucleotide exchange factor eIF2B. Stresses such as nutritional starvation directly target this exchange factor by activation of a kinase, which phosphorylates the alpha subunit of the G protein eIF2. This phosphorylation inhibits the exchange activity of eIF2B thereby down-regulating translation initiation.
Localisation of translation initiation factors
We are interested in how the localisation of factors involved in the translation initiation pathway impact upon the control of translation initiation. We have identified that both eIF2B and eIF2, localise to a cytoplasmic body termed ‘the eIF2B body’. Evidence from live cell imaging techniques such as FRAP (fluorescent recovery after photobleaching) suggest that eIF2 shuttles between the cytoplasm and these bodies and that this rate of shuttling alters in response to stresses which directly target the eIF2B exchange reaction.
Therefore these eIF2B bodies may be sites where eIF2B catalyses the exchange of inactive eIF2xGDP for active eIF2xGTP and therefore form centres within the cells for the regulation of translation initiation. Future studies will aim to determine the precise function, structure and requirement for the eIF2B body within yeast cells.
eIF2B mutations and human genetic diseases
The neurological disorder Leukoencephalopathy with Vanishing white matter (VWM) has been linked to mutations in these subunits of eIF2B. Currently, over 150 missense mutations in eIF2B have been identified however the mechanism of eIF2B involvement in the pathogenesis of this disease remains elusive. Although eIF2B is a global regulator of protein synthesis, the phenotypic effect of the mutations is only observed in oligodendrocytes and astrocytes within the brain.
We have identified eIF2B bodies in mammalian cells and more specifically in cells linked to the pathology of VWM. Using a GFP tagged eIF2Bε subunit, live cell imaging studies suggest that eIF2B bodies are present within human glial cells. The distribution of eIF2B bodies in these cells reveals heterogeneous populations differing in size and abundance. We are currently investigating the functional importance of these eIF2B bodies with respect to translational control and VWM disease.
Hodgson, R.E., Varanda, B.A., Ashe, M.P., Allen, K.E., & Campbell, S. (2019). Cellular eIF2B subunit localisation: implications for the integrated stress response and its control by small molecule drugs. Molecular biology of the cell, 30 (8), 933-1049. http://doi.org/10.1091/mbc.E18-08-0538
Greene, C., Kealy, J., Humphries, M.M., Gong, Y., Hou, J., Hudson, N., ... Campbell, M. (2017). Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia. Molecular psychiatry, 3 (11), 2156-2166. http://doi.org/10.1038/mp.2017.156
Lui, J., Castelli, L.M., Pizzinga, M., Simpson, C.E., Hoyle, N.P., Bailey, K.L., ... Ashe, M.P. (2014). Granules harboring translationally active mRNAs provide a platform for P-Body formation following stress. Cell Reports, 9 (3), 944-954. http://doi.org/10.1016/j.celrep.2014.09.040
Castelli, L.M., Lui, J., Campbell, S., Rowe, W., Zeef, L.A., Holmes, L.E., ... Ashe, M.P. (2011). Glucose depletion inhibits translation initiation via eIF4A loss and subsequent 48S pre-initiation complex accumulation, while the pentose phosphate pathway is co-ordinately up-regulated. Molecular Biology Of The Cell, 22 (18), 3379-3393. http://doi.org/10.1091/mbc.E11-02-0153
Singh, C.R., Watanabe, R., Zhou, D., Jennings, M.D., Fukao, A., Lee, B., ... Asano, K. (2011). Mechanisms of translational regulation by a human eIF5-mimic protein. Nucleic Acids Research, 39 (19), 8314-8328. http://doi.org/10.1093/nar/gkr339
Singh, C.R., Watanabe, R., Zhou, D., Jennings, M.D., Fukao, A., Lee, B., ... Asano, K. (2011). Mechanisms of translational regulation by a human eIF5-mimic protein. Nucleic acids research, 39 (19), 8314-8328.
Taylor, E.J., Campbell, S., Griffiths, C.D., Reid, P.J., Slaven, J.W., Harrison, R.J., ... Ashe, M.P. (2010). Fusel alcohols regulate translation initiation by inhibiting eIF2B to reduce ternary complex in a mechanism that may involve altering the integrity and dynamics of the eIF2B body. Molecular Biology Of The Cell, 21 (13), 2202-2216. http://doi.org/10.1091/mbc.E09-11-0962
Lui, J., Campbell, S., & Ashe, M.P. (2010). Inhibition of translation initiation following gucose depletion in yeast facilitates a arationalization of mRNA content. Biochemical Society Transactions, 38 (4), 1131-1136. http://doi.org/10.1042/BST0381131
Miles, W.O., Jaffray, E., Campbell, S., Takeda, S., Bayston, L.J., Basu, S.P., ... Ashe, H.L. (2008). Medea SUMOylation restricts the signaling range of the Dpp morphogen in the Drosophila embryo. Genes and Development, 22 (18), 2578-2590. http://doi.org/10.1101/gad.494808
James, T.C., Usher, J., Campbell, S., & Bond, U. (2008). Lager yeasts possess dynamic genomes that undergo rearrangements and gene amplification in response to stress. Current genetics, 53 (3), 139-152. http://doi.org/10.1007/s00294-007-0172-8
Rohde, J.R., Campbell, S., Zurita-Martinez, S.A., Cutler, N.S., Ashe, M., & Cardenas, M.E. (2004). TOR controls transcriptional and translational programs via Sap-Sit4 protein phosphatase signaling effectors. Molecular and cellular biology, 24 (19), 8332-8341. http://doi.org/10.1128/MCB.24.19.8332-8341.2004
Holmes, L.E.A., Campbell, S., De Long, S.K., Sachs, A.B., & Ashe, M.P. (2004). Loss of translational control in yeast compromised for the major mRNA decay pathway. Molecular and cellular biology, 24 (7), 2998-3010. http://doi.org/10.1128/MCB.24.7.2998-3010.2004
James, T.C., Campbell, S., Donnelly, D., & Bond, U. (2003). Transcription profile of brewery yeast under fermentation conditions. Journal of applied microbiology, 94 (3), 432-48. http://doi.org/10.1046/j.1365-2672.2003.01849.x
Campbell, S., Li Del Olmo, M., Beglan, P., & Bond, U. (2002). A sequence element downstream of the yeast HTB1 gene contributes to mRNA 3' processing and cell cycle regulation. Molecular and cellular biology, 22 (24), 8415-8425. http://doi.org/10.1128/MCB.22.24.8415-8425.2002
Theses / Dissertations
Norris, K.F. (2018). eIF2B Bodies and their Role in the Control ofProtein Synthesis. (Doctoral thesis). Supervised by Campbell, S. http://doi.org/10.7190/shu-thesis-00129
Karl Norris - The role of membrane associated elF2B complexes in translational regulation
Rachel Hodgson - Characterisation of eIF2B bodies in vanishing white matter disease