Completed Cells, Biochemistry & Physiology Genetics & Molecular Biology

Towards a thorough mechanistic understanding of endosomal cargo sorting.

Funder Wellcome Charity-funded
Recipient organisation University of Bristol
Funding £1.9M
Period Oct 2020 — Sept 2025

In plain English

AI plain-English summary

Every human cell relies on a sorting station called the endosomal network to decide the fate of more than 5,000 different proteins embedded in its membranes. This network shuttles proteins arriving from the cell surface either to the lysosome for destruction or back to the surface for reuse. While scientists understand how cells mark proteins for degradation, the machinery that rescues proteins from that fate and returns them to useful work remains largely unknown. This project targets that gap by studying the retromer pathway, a master controller that in human cells orchestrates the retrieval of over 900 different cargo proteins. The researchers will ask two integrated questions: how the retromer pathway is organised alongside other sorting routes, and how its failure might contribute to neurodegenerative diseases. This is fundamental cell biology with no immediate practical application. However, understanding how cells recycle membrane proteins could eventually illuminate why neurons in diseases such as Parkinson’s or Alzheimer’s lose the ability to clear toxic protein aggregates, potentially pointing toward new therapeutic targets.

View original technical description
An intracellular nexus for regulating the membrane trafficking of many of the 5,000+ integral proteins encoded by the human genome is the endosomal network. Composed of vesicular and tubular early and late endosomes, the network’s principal role is to sort integral proteins (termed ‘cargoes’) arriving from the cell surface and the biosynthetic pathway between two fates: either sorting to the lysosome for degradation, or retrieval from this fate for export to the cell surface, the biosynthetic pathway or other specialised organelles. Whilst the molecular details of degradative cargo sorting have been well documented, those events that conduct cargo retrieval and export remain poorly understood. Our research has sought to fill this fundamental void in metazoan cell biology. A master conductor of endosomal retrieval and export is the retromer pathway - in human cells this orchestrates the sorting of >900 cargoes. Establishing how this pathway functions is central to understanding the evolution, organisation and activity of endosomal sorting. With Wellcome support we will address two integrated questions: - The fundamental question of how the retromer pathway is organised and integrated with other pathways to orchestrate global endosomal cargo sorting. - How understanding of retromer pathway function may provide vital insight into neurodegenerative diseases.

View the original record at the funder ↗

Researchers

Peter Cullen (EPMC Awardee)

Related Research

Grants with similar aims, by meaning.

Defining the role of retromer-like in endolysosomal cargo sorting in health and disease.
Defining the Commander endosomal cargo sorting pathway in health and disease.
Phosphoregulatory mechanisms governing the endosomal retrieval subdomain
Structural characterisation of endosomal trafficking
Endosomal retrieval sub-domain organisation, dynamics and function in human health and disease

Original classification

Investigator Award in Science

Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.