Regulation of CTLA-4 recycling by LRBA and Rab11.
Regulation of CTLA-4 recycling by LRBA and Rab11.
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通过LRBA和Rab 11调节CTLA-4再循环。
DOI：
10.1111/imm.13343
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发表时间：
2021-09
期刊：
影响因子：
6.4
通讯作者：
Sansom DM
中科院分区：
文献类型：
--
作者：
Janman D;Hinze C;Kennedy A;Halliday N;Waters E;Williams C;Rowshanravan B;Hou TZ;Minogue S;Qureshi OS;Sansom DM
CTLA-4是T细胞免疫反应的重要调节因子，其细胞内转运是其表达的标志。由于LRBA缺乏导致的CTLA-4运输缺陷会在人类中引起深刻的自身免疫。CTLA-4通过依赖于笼蛋白的途径迅速内化，随后是特征不佳的循环和降解命运。在这里，我们探索操纵Rab GTP酶和LRBA对CTLA-4表达的影响，以确定这些蛋白如何影响CTLA-4的运输。我们观察到，在HeLa和Jurkat细胞中，CTLA-4分布在由Rab5、Rab7和Rab11标记的几个隔室中。显性负(DN)抑制Rab5导致细胞表面CTLA-4表达增加，内化和降解减少。我们还观察到结构性活性(CA)Rab11增加，而dN Rab11通过影响CTLA-4循环而降低CTLA-4的表面表达，表明CTLA-4与其他循环受体如EGFR有相似之处。此外，我们还研究了操纵LRBA和Rab11对CTLA-4贩运的影响。在Jurkat细胞中，LRBA缺乏与CTLA-4循环明显受损和降解增加有关，这不能通过表达CA Rab11来纠正。此外，LRBA缺乏降低了CTLA-4与Rab11的共定位，表明LRBA位于Rab11的上游。这些结果表明，通过将CTLA-4输送到Rab11回收隔室，需要LRBA才能有效地回收CTLA-4，而在没有它的情况下，CTLA-4无法回收并经历降解。CTLA-4的正确运输是其功能所必需的，而LRBA等蛋白质的突变会导致CTLA-4缺乏症。在这里，我们详细介绍了参与CTLA-4运输的细胞内途径，使用结构性活性和显性负性Rab GTP酶来探讨CTLA-4和LRBA之间的关系。我们的数据表明，CTLA-4的循环强烈依赖于Rab11的活性，LRBA功能可能位于Rab11的上游。
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. Correct trafficking of CTLA‐4 is required for its function and mutations in proteins such as LRBA lead to CTLA‐4 deficiency disorders. Here we detail the intracellular pathways involved in CTLA‐4 trafficking using constitutively active and dominant negative Rab GTPases to probe the relationship between CTLA‐4 and LRBA. Our data show CTLA‐4 recycling is strongly dependent on Rab11 activity and that LRBA function is likely upstream of Rab11.
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DOI：
10.1083/jcb.149.4.901
发表时间：
2000-05-15
期刊：
The Journal of cell biology
影响因子：
--
作者：
Sönnichsen B;De Renzis S;Nielsen E;Rietdorf J;Zerial M
通讯作者：
Zerial M
DOI：
10.1126/science.1202947
发表时间：
2011-04-29
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Qureshi OS;Zheng Y;Nakamura K;Attridge K;Manzotti C;Schmidt EM;Baker J;Jeffery LE;Kaur S;Briggs Z;Hou TZ;Futter CE;Anderson G;Walker LS;Sansom DM
通讯作者：
Sansom DM
影响因子：
9.8
作者：
Lopez-Herrera, Gabriela;Tampella, Giacomo;Grimbacher, Bodo
通讯作者：
Grimbacher, Bodo
影响因子：
20.3
作者：
Hou, Tie Zheng;Verma, Nisha;Sansom, David M.
通讯作者：
Sansom, David M.
影响因子：
3.7
作者：
Kaur, Satdip;Qureshi, Omar S.;Sansom, David M.
通讯作者：
Sansom, David M.