Regulation of CTLA-4 recycling by LRBA and Rab11.

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. This article is protected by copyright. All rights reserved.

Citation

Daniel Janman, Claudia Hinze, Alan Kennedy, Neil Halliday, Erin Waters, Cayman Williams, Behzad Rowshanravan, Tie Zheng Hou, Shane Minogue, Omar S Qureshi, David M Sansom. Regulation of CTLA-4 recycling by LRBA and Rab11. Immunology. 2021 May 07

PMID: 33960403

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