期刊
IMMUNOLOGY
卷 164, 期 1, 页码 106-119出版社
WILEY
DOI: 10.1111/imm.13343
关键词
CTLA-4; LRBA; Rab GTPase; Rab11; recycling; T cells; trafficking
类别
资金
- BBSRC iCASE studentship
- UCB Pharma
- Wellcome Trust [204798/Z/16, 204798/Z/16/Z]
- Wellcome Trust Clinical PhD studentship award [110297/Z/15/Z]
- Arthritis Research UK [21147]
- National Institutes of Health Research (NIHR) University College London Biomedical Research Centre
- NIHR Rare Disease Translational Research Collaboration
- Wellcome Trust Investigator Award
- Wellcome Trust [204798/Z/16/Z, 110297/Z/15/Z] Funding Source: Wellcome Trust
CTLA-4 is distributed across different compartments marked by Rab GTPases, and manipulation of these GTPases affects its expression and trafficking. LRBA deficiency leads to ineffective recycling of CTLA-4 and degradation.
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 internalizes via a clathrin-dependent pathway followed by poorly characterized 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 internalization 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 on 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 colocalization 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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