Projects per year
Abstract
CTLA-4 is an essential inhibitor of T cell immune responses. At steady state, most CTLA-4 resides in intracellular compartments due to constitutive internalisation mediated via a tyrosine based endocytic motif (YVKM) within the cytoplasmic domain. This domain is highly conserved in mammals suggesting strong selective pressure. In contrast, the C-terminal domain varies considerably in non-mammals such as fish, xenopus and birds. We compared the ability of the C-terminus of these species to direct the trafficking of CTLA-4 with human CTLA-4. Using a chimeric approach, endocytosis was found to be conserved between human, xenopus and chicken CTLA-4 but was reduced substantially in trout CTLA-4, which lacks the conserved YXXM motif. Nevertheless, we identified an alternative YXXF motif in trout CTLA-4 that permitted limited endocytosis. Post-internalisation, CTLA-4 was either recycled or targeted for degradation. Human and chicken CTLA-4, which contain a YVKM motif, showed efficient recycling compared to xenopus CTLA-4 which contains a less efficient YEKM motif. Specific mutation of this motif in human CTLA-4 reduced receptor recycling. These findings suggest evolutionary development in the endocytic and recycling potential of CTLA-4, which may facilitate more refined functions of CTLA-4 within the mammalian immune system.
Original language | English |
---|---|
Article number | e60903 |
Journal | PLoS ONE |
Volume | 8 |
Issue number | 4 |
DOIs | |
Publication status | Published - 2 Apr 2013 |
Fingerprint
Dive into the research topics of 'Comparison of the intracellular trafficking itinerary of ctla-4 orthologues'. Together they form a unique fingerprint.Projects
- 1 Finished
-
What is the Molecular Basis of CTLA-4 Trans-Endocytosis?
Sansom, D. (Principal Investigator) & Walker, L. (Co-Investigator)
Biotechnology & Biological Sciences Research Council
1/05/10 → 30/04/14
Project: Research Councils