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Regulation of CTLA-4 recycling by LRBA and Rab11.

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). Green open access

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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.

Type: Article
Title: Regulation of CTLA-4 recycling by LRBA and Rab11.
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/imm.13343
Publisher version: https://doi.org/10.1111/imm.13343
Language: English
Additional information: This article is protected by copyright. All rights reserved. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: CTLA-4, LRBA, Rab GTPase, Rab11, T cells, recycling, trafficking
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Department of Education
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inflammation
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Inst for Liver and Digestive Hlth
URI: https://discovery.ucl.ac.uk/id/eprint/10128160
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