Janman, D;
Hinze, C;
Kennedy, A;
Halliday, N;
Waters, E;
Williams, C;
Rowshanravan, B;
... Sansom, DM; + view all
(2021)
Regulation of CTLA-4 recycling by LRBA and Rab11.
Immunology
10.1111/imm.13343.
(In press).
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Abstract
CTLA-4 is an essential regulator of T cell immune responses whose intracellular trafficking is a hallmark of its expression. Defects in CTLA-4 trafficking due to LRBA deficiency cause profound autoimmunity in humans. CTLA-4 rapidly internalises via a clathrin-dependent pathway followed by poorly characterised recycling and degradation fates. Here we explore the impact of manipulating Rab GTPases and LRBA on CTLA-4 expression to determine how these proteins affect CTLA-4 trafficking. We observe that CTLA-4 is distributed across several compartments marked by Rab5, Rab7 and Rab11 in both Hela and Jurkat cells. Dominant negative (DN) inhibition of Rab5 resulted in increased surface CTLA-4 expression and reduced internalisation and degradation. We also observed that constitutively active (CA) Rab11 increased, whereas DN Rab11 decreased, CTLA-4 surface expression via an impact on CTLA-4 recycling, indicating CTLA-4 shares similarities with other recycling receptors such as EGFR. Additionally, we studied the impact of manipulating both LRBA and Rab11 CTLA-4 trafficking. In Jurkat cells LRBA deficiency was associated with markedly impaired CTLA-4 recycling and increased degradation that could not be corrected by expressing CA Rab11. Moreover LRBA deficiency reduced CTLA-4 co-localisation with Rab11 suggesting that LRBA is upstream of Rab11. These results show that LRBA is required for effective CTLA-4 recycling by delivering CTLA-4 to Rab11 recycling compartments and in its absence CTLA-4 fails to recycle and undergoes degradation.
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