Project Reference: TRG27-PAT-HL1

Project title: Ubiquitin-dependent regulation of secretory trafficking in dopaminergic neurons

Project outline

How cells sort thousands of different proteins to the correct destination, simultaneously and with remarkable accuracy, is one of the most fundamental unsolved questions in cell biology. Central to this is the secretory pathway, through which newly synthesised proteins are processed, sorted at the Golgi apparatus, and dispatched to their correct locations. Understanding how this pathway is regulated is essential for understanding how cells maintain organisation and function.

This project investigates how ubiquitin, a small protein modifier, controls secretory trafficking. Ubiquitin is attached to target proteins by E3 ubiquitin ligases, and these modifications can profoundly alter how a target protein behaves or where it ends up in the cell. FBXO7 is an E3 ligase subunit whose substrates point strongly towards roles in intracellular trafficking, yet how it regulates the secretory pathway and through which molecular targets remains unknown.

Neurons are an ideal system in which to study this question. They are among the most highly polarised cells in the body, facing extreme demands on their trafficking machinery to deliver cargo over vast distances to axons and synapses. How the secretory pathway is regulated in this context, and how ubiquitin modifications contribute to that regulation, is poorly understood.

This PhD project will use human stem cell-derived neurons to investigate how FBXO7 controls secretory trafficking. Live-cell imaging approaches, including RUSH assays that allow cargo to be released and tracked in real time, will reveal where and when the pathway is regulated. Proteomics will identify the molecular targets of FBXO7's ubiquitin-tagging activity within the secretory pathway, and functional experiments will determine how these modifications control trafficking through the Golgi and onward to the cell surface, advancing our understanding of cell biology.

Principal Supervisor

Professor Heike Laman

Email address: hl316@cam.ac.uk

Department / Partner Institute: Pathology

Website: https://www.laman-lab.path.cam.ac.uk/

BBSRC strategic theme

Understanding the rules of life