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The discovery of 'retriever' reveals new insight into human disease

15 September 2017

Bristol Biochemists have made the exciting discovery of a previously unrecognised multi-protein complex that plays a central role in controlling the delivery of proteins to the cell surface. The study of this complex, which they have called “retriever”, will pave the way for further understanding how delivery of proteins to the cell surface is perturbed in a variety of human diseases.

Every cell is defined by the presence of a cell surface membrane. This serves to encapsulate an intracellular space that provides a controlled environment for the complex biochemical processes that define living cells such as metabolism and the replication and interpretation of genetic material. In all eukaryotic cells, from the relatively primitive single cell found in yeast through to the more complex multi-cellular system found in a human tissue, the protein content of the cell surface is constantly undergoing a process of dynamic remodelling. Such remodelling allows the cell to respond to its constantly changing environment. A major and fundamental question in eukaryotic cell biology relates to the question of how cells can precisely control the protein content, and hence function of their cell surface. This regulation is highly relevant to human cells as de-regulation of this process is known to play a role in many human diseases ranging from cancer, diabetes and neurological disorders through to viral and bacterial infection.

In a study recent published in the leader international journal Nature Cell Biology, the laboratory of Peter Cullen has described the discovery of an ancient and highly conserved multi-protein assembly that plays a major role in controlling the remodelling of the cell surface protein content of human cells. In discovering this complex, which they have call "retriever", the laboratory has provided insight into human disease that include neurological disorders and blood cholesterol homeostasis. They also show that retriever is a target for the human papillomavirus during the infectivity and replication lifecycle of this pathogen.

As Pete highlights, "Our discovery of retriever is providing an exciting new avenue through which to study the basic question of how human cells regulate the functionality of their cell surface and how this control is lost in human disease".

Arising from their discovery of retriever, Pete’s laboratory has been awarded a £1.8 million grant from the UK-based Medical Research Council to further define the role of retriever in human cell biology.

"These are exciting times for our research in Bristol. With collaborators from the US, Europe and Australia, the generous funding from the Medical Research Council will allow us to undertake a programme of work aimed at precisely defining the role of retriever. By increasing this basic knowledge we hope to provide new insight into the molecular defects that underlie a number of important human diseases".

Further information

Paper:

'Retriever is a multi-protein complex for retromer-independent endosomal cargo recycling' by McNally KE, Faulkner R, Steinberg F, Gallon M, Ghai R, Pim D, Langton P, Pearson N, Danson CM, Nägele H, Morris LL, Singla A, Overlee BL, Heesom KJ, Sessions R, Banks L, Collins BM, Berger I, Billadeau DD, Burstein E, Cullen PJ in Nature Cell Biology

doi: 10.1038/ncb3610 (2017).

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