Synaptotagmin 3 deficiency in T cells impairs recycling of the chemokine receptor CXCR4 and thereby inhibits CXCL12 chemokine-induced migration
Synaptotagmin 3 deficiency in T cells impairs recycling of the chemokine receptor CXCR4 and thereby inhibits CXCL12 chemokine-induced migration
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DOI：
10.1242/jcs.03328
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发表时间：
2007-01-15
影响因子：
4
通讯作者：
Roos, Ed
中科院分区：
文献类型：
--
作者：
Masztalerz, Agnieszka;Zeelenberg, Ingrid S.;Roos, Ed
突触结合蛋白调节囊泡运输和囊泡与膜的融合-这一过程与细胞迁移有关。因此，我们假设突触结合蛋白在T细胞迁移中发挥作用。在synaptotagmin 1-11中，我们发现synaptotagmin 3（SYT 3）是唯一在T细胞中表达的。CXCR 4触发的迁移被反义突触结合蛋白3 mRNA和分离的C2B结构域抑制，已知C2B结构域损害所有突触结合蛋白的寡聚化，但不被结合Ca 2+但不阻断寡聚化的C2B突变体抑制。C2B结构域还阻断CXCR 4触发的肌动蛋白聚合和侵袭。然而，CXCR 4依赖性粘附在流动不受影响。令人惊讶的是，我们发现几乎没有或没有SYT 3存在于质膜附近，但它主要位于多泡体中，其中也含有大量的CXCR 4。受损的SYT 3功能阻断了CXCR 4的再循环，从而导致CXCR 4的表面水平降低。通过过度表达CXCR 4恢复迁移。我们得出结论，STT 3是必不可少的CXCR 4在T细胞中的回收，从而维持高水平的CXCR 4表面所需的迁移。
Synaptotagmins regulate vesicle trafficking and fusion of vesicles with membranes - processes that have been implicated in cell migration. We therefore hypothesized that synaptotagmins play a role in T-cell migration. Amongst synaptotagmins 1-11, we found synaptotagmin 3 (SYT3) to be the only one that is expressed in T cells. CXCR4-triggered migration was inhibited by antisense synaptotagmin 3 mRNA and by the isolated C2B domain, known to impair oligomerization of all synaptotagmins, but not by a C2B mutant that binds Ca2+ but does not block oligomerization. The C2B domain also blocked CXCR4-triggered actin polymerization and invasion. However, CXCR4-dependent adhesion in flow was not affected. Surprisingly, we found that little or no SYT3 is present near the plasma membrane but that it is mainly localized in multivesicular bodies, which also contained much of the CXCR4. Impaired SYT3 function blocked CXCR4 recycling and thus led to reduced surface levels of CXCR4. Migration was restored by overexpression of CXCR4. We conclude that STT3 is essential for CXCR4 recycling in T cells and thereby for the maintenance of high CXCR4 surface levels required for migration.