title: Comparison of the intracellular trafficking itinerary of ctla-4 orthologues.
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.
authors.affiliation: The MRC Centre for Immune Regulation, School of Immunity and Infection, University of Birmingham Medical School, Birmingham, United Kingdom.
authors.forename: Satdip
authors.initials: S
authors.lastname: Kaur
authors.forename: Omar S
authors.initials: OS
authors.lastname: Qureshi
authors.forename: David M
authors.initials: DM
authors.lastname: Sansom
mesh_terms: D000818:Animals; D060908:CTLA-4 Antigen / Q000378:metabolism*; D002645:Chickens; D004705:Endocytosis / Q000502:physiology; D006801:Humans; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014337:Trout; D014981:Xenopus
chemical_list: D060908:CTLA-4 Antigen
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