The endosomal network in health and disease
Approximately 25% of the human genome encodes for integral membrane proteins (around 5,500 proteins). Efficient intracellular transport of these proteins, and associated proteins and lipids (together termed ‘cargos’), is essential for organelle biogenesis, maintenance, and quality control. This is an extensive field that encompasses the secretory, endolysosomal and autophagic pathways, all fundamental features of eukaryotic cells. Efficient integration of these transport pathways is essential for cellular organisation and function, with errors leading to numerous diseases including those associated with ageing and neurodegeneration.
To maximise the impact of our science we have focused our efforts on elucidating the molecular mechanisms of cargo sorting through the endolysosomal network. Historically this has been dominated by a focus on describing the molecular details of endocytosis and of cargo sorting into the lysosomal degradative pathway. We have broken new ground by illuminating a ‘black box’ in our knowledge: the molecular details that govern cargo retrieval from the degradative fate and their export and recycling to various compartments. In a reductionist approach we have helped to establish retromer, retriever, the CCC and the WASH complexes as key, evolutionary conserved regulators of endolysosomal cargo retrieval, export and recycling. With continuing evidence that perturbed function of these complexes is observed in sporadic and familial Parkinson’s disease, alongside similar evidence in Alzheimer’s disease, defects in endolysosomal sorting have emerged as major contributing factors to pathogenesis. We seek to achieve a greater molecular understanding of this fundamental cellular process and apply this gained knowledge to accelerate the identification of novel drug and diagnostics targets for these, and other disorders.
McGough IJ, et al: SNX3-retromer requires an evolutionary conserved MON2:DOPEY2:ATP9A complex to mediate Wntless sorting and Wnt secretion. Nature Communications 13:3737 (2018).
Cullen PJ., & Steinberg F: To degrade or not to degrade: mechanisms and significance of endocytic recycling. Nature Reviews Molecular Cell Biology doi: 10.1038/s41580-018-0053-7 (2018).
McNally KE, et al: Retriever is a multi-protein complex for retromer-independent endosomal cargo recycling. Nature Cell Biology 19, 1214-1225 (2017).
Simonetti B, et al: Sequence-dependent cargo recognition by SNX-BARs mediates retromer-independent transport of the CI-MPR. Journal of Cell Biology 216, 3695-3712 (2017).
McMillan KJ, et al: Atypical Parkinsonism-associated retromer mutant alters endosomal sorting of specific cargo proteins. Journal of Cell Biology 214, 389-399 (2016).