Role of the CTLA-4 C-terminus in regulating its intracellular trafficking

Kaur, Satdip (2014). Role of the CTLA-4 C-terminus in regulating its intracellular trafficking. University of Birmingham. Ph.D.

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Abstract

CTLA-4 is an important inhibitor of T cell immune responses. The location of CTLA-4 in intracellular vesicles is the most dominating aspect of its biology, yet the significance of this at the functional level remains to be completely understood. I have therefore investigated the role of the CTLA-4 cytoplasmic domain in the intracellular trafficking of the receptor with particular emphasis on sorting signals encoded within this domain. We found that CTLA-4 was located in punctate intracellular vesicles in transfected cells, activated T cells and in regulatory T cells. CTLA-4 internalisation from the cell surface was clathrin dependent and was driven by the YVKM motif encoded within the cytoplasmic domain. Post-internalisation CTLA-4 colocalised with markers of late endosomes. Since the degradation process may serve as one of the mechanisms to regulate CTLA-4 expression we investigated this further and found that ubiquitination of intracellular lysine residues targets CTLA-4 to lysosomes. The ability of CTLA-4 to recycle was dependent on the YVKM motif and subtle changes in this motif reduced recycling efficiency. Moreover, in the absence of lysine residues CTLA-4 recycling was enhanced. CTLA-4 transendocytosis was conserved through evolution but the exact sorting signals required for this function remain to be identified. Overall this thesis emphasises the importance of the CTLA-4 cytoplasmic domain in regulating its intracellular trafficking.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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