Regulation of bacterial adherence to human cells by ZDHHC5-mediated S-acylation of cell surface proteins.

Details

This project will investigate the role of ZDHHC5, a cell surface-localised protein S-acyltransferase, in regulating cell adhesion and bacterial adherence to human cells. ZDHHC5 is one of 23 human DHHC enzymes responsible for attaching fatty acids to proteins, a process known as S-acylation (or palmitoylation). This modification is reversible and dynamically regulates protein trafficking, stability, and function. We hypothesise that ZDHHC5-mediated S-acylation of key adhesion proteins is a crucial regulatory mechanism for bacterial adherence to human cells.

The project aims to identify and quantify the specific protein substrates of ZDHHC5 that are involved in cell-cell adhesion, as cell adhesion pathways are often commandeered for bacterial adherence to host cells. The project will also determine if these protein substrates are utilised in cell-bacterial adhesion and investigate how ZDHHC5-mediated S-acylation affects bacterial binding to human cells.

This project will utilise a combination of molecular and cell biology approaches, microbiology and advanced quantitative proteomic methods. ZDHHC5 knockout cells will be used to study the perturbed cell surface proteome and how this leads to a bacterial adherence phenotype. Direct S-acylation substrates of ZHHC5 will be identified using a mass spectrometry-based proteomics method that we have developed. Specific proteins identified from this screen will be validated using siRNA-mediated knockdown and CRISPR knockout in bacterial adherence assays to determine which specific cell surface proteins mediate interactions with bacteria.

Understanding the mechanism by which ZDHHC5 regulates interactions between cells and how it controls bacterial adherence and traversal will help to develop new strategies to combat infectious diseases, especially in the face of growing antibiotic resistance. It would enable the creation of novel therapeutic and preventative measures that target the initial, critical step of infection.

Funding Notes

Self-Funded students only, you will need to have your own funding.

First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University’s application form using the following link:

https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information.